Derivatives of 4-aminopiperidine and their use as a medicament

ABSTRACT

A subject of the present application is new derivatives of 4-aminopiperidines of formula 
                         
in which R 1 , R 2  and R 3  represent various radical, and their preparation processes by synthetic methods in parallel in liquid and solid phase. These products having a good affinity with certain sub-types of somatostatin receptors, they are particularly useful for treating the pathological states or diseases in which one (or more) somatostatin receptors are involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No.12/151,115, filed May 2, 2008, which is a division of U.S. patentapplication Ser. No. 11/122,293 filed May 4, 2005, now U.S. Pat. No.7,393,861, which is a division of U.S. patent application Ser. No.10/130,924, filed May 23, 2002, now U.S. Pat. No. 7,115,634, which isthe national phase application of PCT/FR00/03497, filed Dec. 13, 2000,which claims the benefit of FR99/15724, filed Dec. 14, 1999, thecontents of all of which are hereby incorporated by reference as iffully set forth herein.

FIELD OF THE INVENTION

A subject of the present application is new derivatives of4-aminopiperidines and their preparation processes by synthetic methodsin parallel in liquid and solid phase. These products having a goodaffinity with certain sub-types of somatostatin receptors, they areparticularly useful for treating the pathological states or diseases inwhich one (or more) somatostatin receptors are involved.

BACKGROUND OF THE INVENTION

Somatostatin (SST) is a cyclic tetradecapeptide which was isolated forthe first time from the hypothalamus as a substance which inhibits thegrowth hormone (Brazeau P. et al., Science 1973, 179, 77-79). It alsooperates as a neurotransmitter in the brain (Reisine T. et al.,Neuroscience 1995, 67, 777-790; Reisine T. et al., Endocrinology 1995,16, 427-442). Molecular cloning has allowed it to be shown that thebioactivity of somatostatin depends directly on a family of fivereceptors linked to the membrane.

The heterogeneity of the biological functions of somatostatin has led tostudies which try to identify the structure-activity relationships ofpeptide analogues on somatostatin receptors, which has led to thediscovery of 5 sub-types of receptors (Yamada et al., Proc. Natl. Acad.Sci. U.S.A, 89, 251-255, 1992; Raynor, K. et al, Mol. Pharmacol., 44,385-392, 1993). The functional roles of these receptors are currentlybeing actively studied. The affinities with different sub-types ofsomatostatin receptors have been associated with the treatment of thefollowing disorders/diseases. Activation of sub-types 2 and 5 has beenassociated with suppression of the growth hormone (GH) and moreparticularly with that of adenomas secreting GH (acromegalia) and thosesecreting hormone TSH. Activation of sub-type 2 but not sub-type 5 hasbeen associated with the treatment of adenomas secreting prolactin.Other indications associated with the activation of sub-types ofsomatostatin receptors are the recurrence of stenosis, inhibition of thesecretion of insulin and/or of glucagon and in particular diabetesmellitus, hyperlipidemia, insensiblity to insulin, Syndrome X,angiopathy, proliferative retinopathy, Dawn phenomenon and nephropathy;inhibition of the secretion of gastric acid and in particular pepticulcers, enterocutaneous and pancreaticocutaneous fistulae, irritablecolon syndrome, dumping syndrome, aqueous diarrhea syndrome, diarrheaassociated with AIDS, diarrhea induced by chemotherapy, acute or chronicpancreatitis and secretory gastrointestinal tumors; the treatment ofcancer such as hepatomas; the inhibition of angiogenesis, the treatmentof inflammatory disorders such as arthritis; chronic rejection ofallografts; angioplasty; the prevention of bleeding of grafted vesselsand gastrointestinal bleeding. The agonists of somatostatin can also beused to reduce the weight of a patient.

Among the pathological disorders associated with somatostatin (Moreau J.P. et al., Life Sciences 1987, 40, 419; Harris A. G. et al., TheEuropean Journal of Medicine, 1993, 2, 97-105), there can be mentionedfor example: acromegalia, hypophyseal adenomas, Cushing's disease,gonadotrophinomas and prolactinomas, catabolic side-effects ofglucocorticoids, insulin dependent diabetes, diabetic retinopathy,diabetic nephropathy, hyperthyroidism, gigantism, endocrinicgastroenteropancreatic tumors including carcinoid syndrome, VIPoma,insulinoma, nesidioblastoma, hyperinsulinemia, glucagonoma, gastrinomaand Zollinger-Ellison's syndrome, GRFoma as well as acute bleeding ofthe esophageal varices, gastroesophageal reflux, gastroduodenal reflux,pancreatitis, enterocutaneous and pancreatic fistulae but alsodiarrheas, refractory diarrheas of acquired immunodeficiency syndrome,chronic secretary diarrhea, diarrhea associated with irritable bowelsyndrome, disorders linked with gastrin releasing peptide, secondarypathologies with intestinal grafts, portal hypertension as well ashemorrhages of the varices in patients with cirrhosis, gastro-intestinalhemorrhage, hemorrhage of the gastroduodenal ulcer, Crohn's disease,systemic scleroses, dumping syndrome, small intestine syndrome,hypotension, scleroderma and medullar thyroid carcinoma, illnesseslinked with cell hyperproliferation such as cancers and moreparticularly breast cancer, prostate cancer, thyroid cancer as well aspancreatic cancer and colorectal cancer, fibroses and more particularlyfibrosis of the kidney, fibrosis of the liver, fibrosis of the lung,fibrosis of the skin, also fibrosis of the central nervous system aswell as that of the nose and fibrosis induced by chemotherapy, and othertherapeutic fields such as, for example, cephaleas including cephaleaassociated with hypophyseal tumors, pain, panic attacks, chemotherapy,cicatrization of wounds, renal insufficiency resulting from delayeddevelopment, obesity and delayed development linked with obesity,delayed uterine development, dysplasia of the skeleton, Noonan'ssyndrome, sleep apnea syndrome, Graves' disease, polycystic disease ofthe ovaries, pancreatic pseudocysts and ascites, leukemia, meningioma,cancerous cachexia, inhibition of H pylori, psoriasis, as well asAlzheimer's disease. Osteoporisis can also be mentioned.

The applicants found that the compounds of general formula describedhereafter have an affinity and a selectivity for the somatostatinreceptors. As somatostatin and its peptide analogues often have a poorbioavailability by oral route and a low selectivity (Robinson, C., Drugsof the Future, 1994, 19, 992; Reubi, J. C. et al., TIPS, 1995, 16, 110),said compounds, non-peptide agonists or antagonists of somatostatin, canbe advantageously used to treat pathological states or illnesses aspresented above and in which one (or more) somatostatin receptors areinvolved. Preferably, said compounds can be used for the treatment ofacromegalia, hypophyseal adenomas or endocrine gastroenteropancreatictumors including carcinoid syndrome.

BRIEF SUMMARY OF THE INVENTION

Therefore a subject of the present invention is the compounds of generalformula

in racemic, enantiomeric form or all combinations of these forms, inwhich:

-   R₁ represents a linear or branched (C₁-C₁₆)alkyl, alkenyl, alkynyl,    —(CH₂)_(m)—Y—Z₁₁ or —(CH₂)_(m)—Z₁₂ radical in which    -   Z₁₁ represents a (C₁-C₆)alkyl or aryl optionally substituted,    -   Z₁₂ represents cyano, cyclohexenyl, bis-phenyl,        (C₃-C₇)cycloalkyl, optionally substituted (C₃-C₇)        heterocycloalkyl, optionally substituted aryl or optionally        substituted heteroaryl,    -   or Z₁₂ represents a radical of formula

-   or R₁ represents a radical of formula

-   R₂ represents a radical of formula —C(Y)NHX₁, —C(O)X₂ or SO₂X₃;-   R₃ represents the hydrogen atom, an optionally substituted alkyl,    alkenyl, alkynyl, optionally substituted aralkyl, optionally    substituted heteroarylalkyl radical, or a radical of formula    —C(Y)—NHX₁, —(CH₂)_(n)—C(O)X₂, SO₂X₃ or

-   X₁ represents a linear or branched (C₁-C₁₅)alkyl, alkenyl, alkynyl,    —(CH₂)_(m)—Y—Z₂₁ or —(CH₂)_(p)Z₂₂ radical in which    -   Z₂₁ represents a (C₁-C₆)alkyl    -   Z₂₂ represents cyclohexenyl, indanyl, bis-phenyl,        (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, mono- or        di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally        substituted,    -   or Z₂₂ represents a radical of formula

-   X₂ represents a linear or branched (C₁-C₁₀)alkyl radical, an alkenyl    radical optionally substituted by a phenyl radical (the phenyl    radical being itself optionally substituted), an alkynyl radical, or    a radical of formula —(CH₂)_(m)—W—(CH₂)_(q)—Z₂₃ or —(CH₂)_(p)—U—Z₂₄    in which    -   Z₂₃ represents a (C₁-C₆)alkyl or aryl optionally substituted;    -   Z₂₄ represents alkyl, cyclohexenyl, bis-phenyl,        (C₃-C₇)cycloalkyl optionally substituted,        (C₃-C₇)heterocycloalkyl, cyano, amino, mono or di-alkylamino, or        aryl or heteroaryl optionally substituted,    -   or Z₂₄ represents a radical of formula

-   or X₂ represents a radical represented below:

-   where the protective group (PG) represents H or    tert-butyloxycarbonyl;-   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, an alkenyl    radical optionally substituted by a phenyl radical (the phenyl    radical being itself optionally substituted), CF₃, or —(CH₂)_(p)Z₂₅    in which    -   Z₂₅ represents aryl or heteroaryl optionally substituted,-   or X₃ represents a radical of formula

Optionally substituted by one or more halo radicals identical ordifferent;

-   Y represents an oxygen or sulphur atom;-   W represents an oxygen or sulphur atom, or SO₂;-   U represents a covalent bond or the oxygen atom;-   n is an integer from 0 to 4;-   m is an integer from 1 to 6;-   p is an integer from 0 to 6;-   q is an integer from 0 to 2,    or their addition salts with pharmaceutically acceptable mineral or    organic acids, with the exclusion of compounds of general formula I    wherein R₁ represents the radical alkyle, alkenyle or benzyle, R₂ an    optionally substituted benzyloxy and R₃ aralkyle.

A more particularly subject of the invention is the products of generalformula I as defined above, characterized in that

-   i) the substituent or substituents which can be carried by the aryl    radicals represented by Z₁₁ and Z₁₂ and heteroaryl represented by    Z_(t2) are chosen independently from the fluoro, chloro, bromo,    iodo, alkyl, alkoxy, alkylthio, —CF₃, —OCF₃, phenyl, phenoxy,    aminosulphonyl radicals;-   ii) the substituent or substituents which can be carried by the    heterocycloalkyl radical represented by Z₁₂ are chosen independently    from the oxy and alkyl radicals;-   iii) the substituent or substituents which can be carried by the    aryl and heteroaryl radicals represented by Z₂₂ are chosen    independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl,    alkoxy, alkylthio, CF₃, OCF₃, nitro, cyano, azido, aminosulphonyl,    piperidinosulphonyl, mono- or di-alkylamino, —C(O)—O-alkyl,    —C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the    phenyl radical being able to be substituted;-   iv) the substituent or substituents which can be carried by the aryl    radicals represented by Z₂₃ and Z₂₄, cycloalkyl and heteroaryl    represented by Z₂₄ are chosen independently from the fluoro, chloro,    bromo, iodo, alkyl, alkoxy, alkylthio, CF₃, OCF₃, OCHF₂, SCF₃,    nitro, cyano, azido, hydroxy, —C(O)O-alkyl, —O—C(O)-alkyl,    —NH—C(O)-alkyl, alkylsulphonyl, mono- or di-alkylamino, amino,    aminoalkyl, pyrrolyl, pyrxolydinyl or the radicals phenyl, phenoxy,    phenylthio, benzyl, benzyloxy radicals the aryl radical of which is    optionally substituted by one or more alkyl, CF₃ or halo radicals;-   v) the substituent or substituents which can be carried by the aryl    and heteroaryl radicals represented by Z₂₅ are chosen independently    from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, OCF₃,    nitro, cyano, —NH—C(O)-alkyl, alkylsulphonyl, amino, mono- and    di-alkylamino, phenyl, pyridino radicals;-   vi) the substituent which can be carried by the alkyl radical    represented by R₃ is the cyano radical;-   vii) the substituent or substituents which can be carried by the    aralkyl radical represented by R₃ are chosen independently from the    fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, OCF₃, OCHF₂, SCF₃,    SCHF₂, nitro, cyano, —C(O)O-alkyl, alkylsulphonyl, thiadiazolyl    radicals, or the phenyl and phenoxy radicals the phenyl radical of    which is optionally substituted by one or more halo radicals;-   viii) the substituent or substituents which can be carried by the    heteroarylalkyl radical represented by R₃ are chosen independently    from the fluoro, chloro, bromo or nitro radicals.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In the definitions indicated above, the expression halo represents thefluoro, chloro, bromo or iodo radical, preferably chloro, fluoro orbromo. The expression alkyl (when it is not specified otherwise),preferably represents a linear or branched alkyl radical having 1 to 6carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl, pentyl or amyl, isopentyl,neopentyl, hexyl or isohexyl radicals. Among the alkyl radicalscontaining 1 to 15 carbon atoms, there can be mentioned the alkyls asdefined above but also the heptyl, octyl, nonyl, decyl, dodecyl,tridecyl or pentadecyl radicals.

By alkenyl, when it is not specified otherwise, is understood a linearor branched alkyl radical containing 1 to 6 carbon atoms and having atleast one unsaturation (double bond), such as for example vinyl, allyl,propenyl, butenyl or pentenyl. By alkynyl, when it is not specifiedotherwise, is understood a linear or branched alkyl radical containing 1to 6 carbon atoms and having at least one double unsaturation (triplebond) such as for example an ethynyl, propargyl, butynyl or pentynylradical.

The term cycloalkyl designates a monocyclic carbon system comprising 3to 7 carbon atoms, and preferably the cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl rings. The expression heterocycloalkyldesignates a saturated cycloalkyl containing 2 to 7 carbon atoms and atleast one heteroatom. This radical can contain several identical ordifferent heteroatoms. Preferably, the heteroatoms are chosen fromoxygen, sulphur or nitrogen. As examples of a heterocycloalkyl, therecan be mentioned the pyrrolidine, pyrrolidinone, imidazolidine,pyrrazolidine, isothiazolidine, thiazolidine, isoxazolidine, piperidine,piperazine or morpholine ring.

The alkoxy radicals can correspond to the alkyl radicals indicated abovesuch as for example the methoxy, ethoxy, propyloxy or isopropyloxyradicals but also linear, secondary or tertiary butoxy, pentyloxy. Theterm lower alkylthio preferably designates the radicals in which thealkyl radical is as defined above such as for example methylthioethylthio. The term alkylsulphonyl preferably designates the radicals inwhich the alkyl radical is as defined above.

The expression aryl represents an aromatic radical, constituted by acondensed ring or rings, such as for example the phenyl or naphthylradical. The expression heteroaryl designate an aromatic radical,constituted by a ring or condensed rings, with at least one ringcontaining one or more identical or different heteroatoms chosen fromsulphur, nitrogen or oxygen. As an example of a heteroaryl radical,there can be mentioned the thienyl, furyl, pyrrolyl, imidazolyl,pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl,pyridyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, quinoxalinyl,benzothienyl, benzofuryl, indolyl, benzoxadiazoyl radicals.

The terms mono- and di-alkylamino preferably designate the radicals inwhich the alkyl radicals are as defined above, such as for examplemethylamino, ethylamino, dimethylamino: diethylamino or(methyl)(ethyl)amino.

The symbol -> * corresponds to the attachment point of the radical. Whenthe attachment site is not specified on the radical, this signifies thatthe attachment is carried out on one of the sites which are available tothis radical for such an attachment.

A more particular subject of the present invention is the compounds ofgeneral formula I as defined above in which:

-   R₁ represents a linear or branched (C₁-C₆)alkyl radical, the    —(CH₂)_(m)—Y—Z₁₁ or —(CH₂)_(m)—Z₁₂ radical in which    -   Z represents a (C₁-C₆)alkyl,    -   Z₁₂ represents bis-phenyl, (C₃-C₇)cycloalkyl,        (C₃-C₇)heterocycloalkyl optionally substituted, or aryl or        heteroaryl optionally substituted by one or more substituents        chosen independently from the fluoro, chloro, bromo, iodo,        alkyl, alkoxy radicals,    -   or Z₁₂ represents

-   -   Y represents the oxygen atom,

-   or R₁ represents a radical of formula

-   R₂ represents a radical of formula —C(Y)NHX₁, —C(O)X₂ or SO₂X₃ in    which    -   X₁ represents a linear or branched (C₁-C₁₅)alkyl radical, or        —(CH₂)_(p)Z₂₂ in which        -   Z₂₂ represents cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl,            (C₃-C₇)heterocycloalkyl, mono- or di-alkylamino,            —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted            by one or more radicals chosen independently from the            fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF₃,            OCF₃, nitro, cyano, azido, piperidinosulphonyl,            —C(O)—O-alkyl, —C(O)-alkyl, or phenyl radicals,        -   or Z₂₂ represents a radical of formula

-   -   X₂ represents a linear or branched (C₁-C₁₀)alkyl, alkynyl,        —(CH₂)_(m)—W—(CH₂)_(q)—Z₂₃ or —(CH₂)_(p)—U—Z₂₄ radical in which        -   W represents SO₂,        -   U represents a covalent bond,        -   Z₂₃ represents an aryl radical;        -   Z₂₄ represents cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl            optionally substituted by an aminoalkyl, or aryl or            heteroaryl radical optionally substituted by one or more            radicals chosen from fluoro, chloro, bromo, iodo, alkyl,            alkoxy, —CF₃, —OCF₃, SCF₃, hydroxy, —O—C(O)-alkyl, mono- or            di-alkylamino, amino        -   or Z₂₄ represents a radical of formula

-   -   or X₂ represents

-   -   X₃ represents a —(CH₂)_(p)Z₂₅ radical in which Z₂₅ represents an        aryl radical optionally substituted by one or more identical or        different radicals chosen from alkoxy and CF₃,

-   R₃ represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl    radical optionally substituted or a radical of formula —C(Y)—NHX₁,    —C(O)X₂ or SO₂X₃ in which    -   X₁ represents a —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents an aryl radical optionally substituted by one            or more radicals chosen independently from the fluoro,            chloro, bromo, iodo, alkyl, alkoxy, CF₃, nitro, phenoxy            radicals;    -   X₂ represents the vinyl radical substituted by a phenyl, the        phenyl radical being itself optionally substituted by one or        more halo, or —(CH₂)_(p)—U—Z₂₄ radicals in which        -   Z₂₄ represents alkyl, (C₃-C₇)cycloalkyl,            (C₃-C₇)heterocycloalkyl, bis-phenyl, amino, mono or            di-alkylamino, or aryl or heteroaryl optionally substituted            by one or more radicals chosen from alkoxy, bromo, chloro,            fluoro, hydroxy, CF₃, nitro, amino, mono- and di-alkylamino,            pyrrolyl.    -   or Z₂ represents a radical of formula

-   -   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, the        vinyl radical substituted by a radical (the phenyl radical being        itself optionally substituted), CF₃, or —(CH₂)_(p)Z₂₅ in which        -   Z₂₅ represents aryl or heteroaryl optionally substituted by            one or more substituents chosen independently from the            fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, nitro,            —NH—C(O)-alkyl, mono- and di-alkylamino radicals.

-   Preferentially, R₁ represents a linear or branched (C₁-C₆)alkyl    radical, the —(CH₂)_(m)—Y—Z₁₁ or —(CH₂)_(m)—Z₁₂ radical in which    -   Z₁₁ represents a (C₁-C₆)alkyl,    -   Z₁₂ represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl        substituted by the oxy radical, or the phenyl, piperazinyl,        pyridinyl and indolyl radicals which are optionally substituted        by one or more substituents chosen independently from the bromo,        fluoro, chloro, alkyl, alkoxy, —CF₃, —OCF₃ radicals;    -   or Z₁₂ represents

-   -   Y represents the oxygen atom,

-   or R₁ represents a radical of formula given below:

-   Preferentially, R₂ represents a radical of formula —C(Y)NHX₁,    —C(O)X₂ or SO₂X₃ in which    -   X₁ represents a linear or branched (C₁-C₁₀)alkyl, or        —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents cyclohexyl, cyclohexenyl, bis-phenyl,            morpholino, piperidino, mono- or di-alkylamino,            —C(O)—O-alkyl, or phenyl, naphthyl or furyl optionally            substituted by one or more radicals chosen independently            from the fluoro, chloro, bromo, iodo, alkyl, alkoxy,            alkylthio, CF₃, OCF₃, nitro, cyano, azido,            piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl            radicals,        -   or Z₂₂ represents a radical of formula

-   -   X₂ represents an alkyl, alkynyl, —(CH₂)_(m)—W—(CH₂)_(q)—Z₂₃ or        —(CH₂)_(p)Z₂₄ radical in which        -   W represents SO₂;        -   Z₂₃ represents the phenyl radical;        -   Z₂₄ represents cyclohexenyl, bis-phenyl, cyclohexyl            optionally substituted by an aminoalkyl, or phenyl,            naphthyl, benzothienyl, thienyl or indolyl radical            optionally substituted by one or more radicals chosen from            fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF₃, —OCF₃,            SCF₃, hydroxy, —NH—C(O)-alkyl, mono- or di-alkylamino,            amino, or        -   Z₂₄ represents a radical of formula

-   -   or X₂ represents

-   -   X₃ represents a —(CH₂)_(p)Z₂₅ radical in which Z₂₅ represents        the phenyl radical optionally substituted by one or more        identical or different radicals chosen from alkoxy and CF₃,

-   Preferentially, R₃ represents the hydrogen atom, an alkyl, alkenyl    or furyl-methyl radical substituted by one or more nitro radicals,    or a radical of formula —C(Y)—NHX₁, —C(O)X₂ or SO₂X₃ in which    -   X₁ represents a —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents the phenyl or naphthyl radical optionally            substituted by one or more radicals chosen independently            from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃,            nitro, phenoxy radicals,    -   X₂ represents the vinyl radical substituted by a phenyl radical        itself optionally substituted by one or more halo, or        —(CH₂)_(p)—U—Z₂₄ radicals in which        -   Z₂₄ represents alkyl, cyclohexyl, tetrahydrofuryl,            bis-phenyl, amino, mono or di-alkylamino, or phenyl,            indolyl, thienyl, pyridinyl, benzothienyl and furyl            optionally substituted by one or more radicals chosen from            alkoxy, bromo, chloro, fluoro, amino, mono- and            di-alkylamino, nitro, hydroxy, pyrrolyl    -   or X₂ represents a radical of formula

-   -   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, the        vinyl radical substituted by a phenyl, CF₃, or —(CH₂)_(p)Z₂₅        radical in which        -   Z₂₅ represents a phenyl, naphthyl, thienyl, pyrazolyl or            thiazolyl radical optionally substituted by one or more            substituents chosen independently from the fluoro, chloro,            bromo, iodo, alkyl, alkoxy, CF₃, nitro, —NH—C(O)-alkyl,            mono- and di-alkylamino radicals;

-   Very preferentially, R₁ represents the —(CH₂)_(m)Z₁₂ radical in    which m=2 and Z₁₂ represents bis-phenyl or the radical indolyl    substituted by one or more substituents chosen independently from    the alkyl and alkoxy radicals.

-   Very preferentially, R₂ represents the radicals of formula —C(Y)NHX₁    and —C(O)X₂ in which    -   Y represents S;    -   X₁ represents a phenyl radical optionally substituted by one or        more azido radicals.    -   X₂ represents —(CH₂)_(p)Z₂₄ in which        -   p is equal to 1, 2 or 3,        -   Z₂₄ represents cyclohexyl, or phenyl or benzothienyl            optionally substituted by one or more radicals chosen from            fluoro, chloro, bromo, iodo or —CF₃.

-   Very preferentially, R₃ represents the hydrogen atom or the methyl    radical.

The compounds according to the invention can be prepared in solid orliquid phase.

A) SYNTHESES IN LIQUID PHASE VIA THE N-substituted PIPERIDONE A1)Reducing Amination

It is carried out according to the following stage:

in which R represents methyl or Boc and R₁ has the meaning indicatedabove.

The general procedure is as follows: the reducing amination(Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett.1990, 31, 5595-5598; Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;Maryanoff, C. A.; Shah, R. D., J. Org. Chem. 1996, 61, 3849-3862) of theN-substituted piperidone is carried out in anhydrous chlorinatedsolvents such as dichloroethane in the presence of a primary amine (1.1to 1.5 eq.), a reducing agent such as sodium triacetoxyborohydride (1.1to 1.5 eq.) and acetic acid (10% by mass relative to the N-substitutedpiperidone). The reaction mixture is agitated for 1 to 4 hours atambient temperature. In certain cases, a solution of soda (0.1 M) isadded and the mixture is agitated for 20 to 90 minutes. If not, thereaction mixture is washed with a saturated solution of sodiumbicarbonate, with sodium chloride, dried over magnesium sulphate,filtered and concentrated. The desired product is purified by flashchromatography on silica gel.

Preparation 1 tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate(C₂₅H₃₄N₁O₂, M=394.56)

3,3-diphenylpropylamine (5.8 g, 27.5 mmol), sodium triacetoxyborohydride(6.36 g, 30 mmol) and 0.5 ml of acetic acid are added to 5 g (25 mmol)of N-Boc-piperidone in 100 ml of dry dichloroethane. The turbid yellowsolution is agitated at ambient temperature for 1 hour. 50 ml of a sodasolution (0.1 M) is then added and the mixture is agitated for 30minutes. The organic phase is washed with a saturated solution of sodiumbicarbonate, with sodium chloride, dried over magnesium sulphate,filtered and concentrated in order to produce 10 g of a yellow solid.This solid is purified by flash chromatography on silica gel elutingwith a heptane/ethyl acetate mixture (4/1, 3/1, 2/1 then 1/1) then withpure ethyl acetate. The fractions are concentrated under vacuum in orderto produce 5.6 g (yield=57%) of a pale yellow solid.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.27 (m, 8H); 7.16 (m, 2H); 4 (dd, J=6.4 and14 Hz, 3H); 2.73 (m, 2H); 2.55 (m, 3H); 2.26 (q, J=7.6 Hz, 2H); 1.78 (d,J=12 Hz, 2H); 1.45 (s, 9H); 1.15 (qd, J=4.4 and 12.8 Hz, 2H). MS/LC:m/z=395.2 (M+H).

A series of 4-aminosubstituted-1-piperidine was prepared according tothis procedure with the following other R₁ groups:

A2) Functionalization of Piperidines A2a) Syntheses of Ureas andThioureas

The syntheses of ureas and thioureas are implemented according to theprocedure described in the literature (Kaldor, S. W.; Siegel, M. G.;Fritz, J. E.; Dressman, B. A.; Hahn, P. J. Tetrahedron Lett. 1996, 37,7193-7196; Kaldor, S. W.; Fritz, J. E.; Tang, J.; McKinney, E. R.Bioorg. Med. Chem. Lett. 1996, 6, 3041-3044; Booth, R. J.; Hodges, J. C.J. Am. Chem. Soc. 1997, 119, 4882-4886; Flynn, D. L.; Crich. J. Z.;Devraj, R. V.; Hockerman, S. L.; Parlow, J. J.; South, M. S.; toWoodard, S.; J. Am. Chem. Soc. 1997, 119, 4874-4881) following thefollowing diagram:

in which R represents methyl or Boc and X₁ and Y have the meaningindicated above. It should be noted that in the case where R representsBoc, the product thus obtained is a final product corresponding toformula I according to the invention but can also be used as a synthesisintermediate.

The general procedure is as follows: the isocyanate or theisothiocyanate (1.1 to 1.5 eq.) is added to the4-aminosubstituted-1-piperidine in aprotic solvents such asdichloromethane, tetrahydrofuran or dimethylformamide and the mixture isagitated for 45 minutes to 18 hours at ambient temperature. Theaminomethyl resin (Novabiochem, 1.33 mmol/g, 0.2 to 1 eq.) is added andthe mixture is agitated for 45 minutes to 18 hours. In certain cases,the basic ion exchange resin such as IRA-68 (Gayo, L. M.; Suto, M. J.Tetrahedron Lett. 1997, 38, 513-516) can be added. The resins arefiltered and the filtrate is concentrated. Other purifications on silicagel or basic alumina cartridges (500 mg, Interchim) can optionally becarried out.

Example A2atert-butyl-4-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-1-piperidinecarboxylate (C₃₃H₃₈F₃N₃O₃, M=581.68)

246 mg (1.32 mmol) of 3-(trifluoromethyl)phenyl isocyanate is added to asolution of tert-butyl 4-[(3,3-diphenylpropyl)amino]-1-piperidinecarboxylate (470 mg, 1.2 mmol) in 5 ml of dichloromethane. The solutionis agitated for 45 minutes, and the aminomethyl resin (180 mg, 0.36mmol) is added and the reaction medium is again placed on an orbitalshaker for 45 minutes. The resin is filtered and washed withdichloromethane. The filtrate is concentrated in vacuo in order toproduce 610 mg (yield=87%) of a white foam.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.71 (s, 1H); 7.57 (d, 1H); 7.43 (t, 1H);7.26 (m, 10H); 7.15 (m, 1H); 4.1 (m, 3H); 3.97 (dd, J=7.6 and 10 Hz,1H); 3.17 (m, 2H); 2.75 (m, 2H); 2.35 (m, 2H); 1.65 (d, J=12 Hz, 2H);1.46 (s, 9H, tbutyl group); 1.39 (dd, J=2.4 and 10.8 Hz, 2H); 1.29 (s,1H). MS/LC: m/z=582 (M+H).

For the R₁ groups as illustrated in point A1 above, the X₁ groups whichcan be envisaged for the synthesis of ureas (Y═O) according to the aboveprocedure, are the following:

For the R₁ groups as illustrated in point A1 above, the X₁ groups whichcan be envisaged for the synthesis of thioureas (Y═S) according to theabove procedure, are the following:

A2b) Synthesis of Amides from Carboxylic Acids

The syntheses of amides from carboxylic acids are implemented accordingto the following reaction diagram:

in which R represents methyl or Boc and X₂ has the meaning indicatedabove. It should be noted that in the case where R represents Boc, theproduct thus obtained is a final product corresponding to formula Iaccording to the invention but can also be used such as a synthesisintermediate.

The general procedure is as follows: carboxylic acid (1.1 to 2.5 eq.)dissolved in an anhydrous aprotic solvent such as dichloromethane,dimethylformamide or tetrahydrofuran is activated with1-ethyl-3-(3-dimethylaminopropyl) carbodiimide bonded on resin (P-EDC,Novabiochem, 2.33 mmol/g, 1.3 to 3 eq.) (Desai, M. C.; StephensStramiello, L. M. Tetrahedron Lett. 1993, 34, 7685-7688). This mixtureis agitated for 5 to 30 minutes at ambient temperature.4-aminosubstituted-1-piperidine dissolved beforehand in an anhydrousaprotic solvent such as dichloromethane, dimethylformamide ortetrahydrofuran is then added and the reaction mixture is agitated atambient temperature for 1 to 18 hours. In certain cases, basic ionexchange resin (IRA-68, SAX) is added and the mixture is again agitatedat ambient temperature for 1 to 18 hours. The resins are filtered onfrit or on a basic ion exchange resin cartridge (IRA-68, SAX) or on analumina cartridge (500 mg, Interchim).

Example A2b tert-butyl4-{(3,4-dimethoxyphenethyl)[2-(1H-indol-3-yl)acetyl]amino}-1-piperidinecarboxylate (C₃₅H₄₁N₃O₃, M=551.74)

512 mg (1.12 mmol, 1.4 eq.) of P-EDC resin is preswollen indichloromethane. 2-(1H-indol-3-yl)acetic acid (153 mg, 0.875 mmol, 1.1eq.) is added and the mixture is agitated for 10 minutes. Tert-butyl4-[(3,3-diphenylpropyl)amino]-1-piperidine carboxylate (292 mg, 0.8mmol) in tetrahydrofuran is added and the reaction medium is agitatedovernight. 2 spatulas of basic ion exchange resin IRA-68 are added andthe reaction medium is again agitated overnight. The resins are filteredand the filtrate is concentrated under vacuum in order to produce 250 mg(yield=86%) of a pale yellow foam.

NMR ¹H(CD₃OD, 400 MHz) δ: 7.63 (d, J=8 Hz, 1H); 7.44 (d, J=8 Hz, 1H);7.36 (d, J=8 Hz, 1H); 7.26 (d, J=8 Hz, 1H); 7.2 (m, 6H); 7.13 (m, 3H);7.1 (m, 2H); 6.68 (s, 1H); 4-3.75 (m, 4H); 3.65 (s, 1H); 3.2 (m, 1H); 3(m, 1H); 2.75 (m, 1H); 2.26 (m, 3H); 1.6 (m, 2H); 1.44 (s, 9H); 1.13 (m,2H). MS/LC: m/z=552.4 (M+H).

A series of amides was synthesized according to this procedure. The X₂radicals which can be envisaged are the following:

where the protective group (PG) represents H or tert-butyloxycarbonyl.

A3) Syntheses of 4-aminodisubstituted Piperidines

The synthesis of 4-aminodisubstitueted piperidines according to theinvention, can be carried out by acid treatment of the N-Boc compoundsdescribed previously, following the following reaction diagram:

General procedure: two methods were used to carry out the deprotectionin acid media of the ureas, thioureas and amides described previously.The first consists in dissolving the compound in dichloromethane andadding trifluoroacetic acid (5 to 20 eq.) whilst in the second asolution of dilute hydrochloric acid in solvents such as ethyl acetate,dioxane or diethylether (5 to 20 eq.) is used. The reaction medium isagitated for 1 to 4 hours at ambient temperature. In certain cases,dichloromethane is added and the organic phase is washed with asaturated solution of sodium bicarbonate, dried over magnesium sulphate,filtered and concentrated under vacuum in order to isolate the freebase.

Example A3N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea(C₂₈H₃₀F₃N₃O, M=481.57)

1.6 ml (21 mmol, 20 eq.) of trifluoroacetic acid is added to a solutionof tert-butyl 4-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-1-piperidine carboxylate(600 mg, 1.04 mmol) in dichloromethane. The reaction medium is agitatedfor 90 minutes then concentrated. Dichloromethane is added and theorganic phase is washed with a saturated solution of sodium bicarbonate,dried over magnesium sulphate, filtered and concentrated under vacuum inorder to isolate 490 mg (yield=98%) of a white foam.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.7 (s, 1H); 7.55 (d, 1H); 7.44 (1, 1H); 7.28(m, 9H); 7.18 (m, 2H); 4.05 (m, 2H); 3.26 (m, 2H); 3.11 (d, J=10.8 Hz,2H); 2.7 (td, J=2.4 and 12.4 Hz, 2H); 2.38 (q, J=8 Hz, 2H); 1.76 (d,J=10 Hz, 2H); 1.63 (qd, J=4 and 12.4 Hz, 2H). MS/LC: m/z=482.2 (M+H).

A series of 4-aminopiperidines was synthesized according to thisprocedure. The R₁, to X₁ and X₂ radicals which can be envisaged arethose already illustrated in points A1 and A2 above.

B) SYNTHESIS IN SOLID PHASE OF 4-aminopiperidines

4-aminopiperidines were prepared by synthesis in solid phase startingwith Wang resin.

B1) Preparation of the Resin B1a) Preparation of the P-nitrophenylCarbonate Wang Resin

It is carried out according to the following diagram

This resin was prepared from Wang resin (supplied by Bachem orNovabiochem) with a load rate greater than 0.89 mmol/g, following theprocedure described in the literature (Bunin, B. A. The CombinatorialIndex, Academic Press, 1998, p. 62-63; Dressman, B. A.; Spangle, L. A.;Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937-940; Hauske, J. R.; Dorff,P. Tetrahedron Lett. 1995, 36, 1589-1592; Cao, J.; Cuny, G. D.; Hauske,J. R. Molecular Diversity 1998, 3, 173-179): N-methylmorpholine orpyridine and 4-nitrophenyl chloroformate are added successively to theWang resin preswollen in dichloromethane or tetrahydrofuran at ambienttemperature. The mixture is agitated overnight. The resin is washed withtetrahydrofuran, with diethylether and with dichloromethane then driedin vacuo at 50° C. overnight.

B1b) Preparation of the Piperidone Carbamate Resin

It is carried out according to the following diagram

Triethylamine (1 eq.) and the molecular sieve are added to the hydratedpiperidone hydrochloride diluted in dimethylformamide. The mixture isheated until complete dissolution of the ketone. This solution is addedto the p-nitrophenyl carbonate Wang resin (0.05 eq.) preswollen indimethylformamide. After agitation for 24 to 72 hours at ambienttemperature, the resin is filtered then washed several times withdimethylformamide, tetrahydrofuran, diethylether and dichloromethane.

Preparation 2

2.5 g of p-nitrophenyl carbonate Wang resin (load rate of 0.88 mmol/g,2.2 mmol) is preswollen in 100 ml of dimethylformamide. At the sametime, 6.7 g (44 mmol, 20 eq.) of hydrated piperidone hydrochloride, 4.45g (44 mmol, 20 eq.) of triethylamine and three spatulas of molecularsieve are heated in 100 ml of dimethylformamide until completedissolution. The yellowish solution is poured warm onto the resin andthe mixture is agitated for 40 hours at ambient temperature. The resinis filtered then washed with dimethylformamide, tetrahydrofuran,diethylether and dichloromethane (3 times with each solvent) then driedunder vacuum. 2.4 g of pale yellow resin is isolated with a load rate of0.88 mmol/g calculated after elementary analysis of the nitrogen.

B2) Reducing Amination on Solid Support

It is carried out according to the diagram

The general procedure is the following: the primary amine (5 to 10 eq.)is added to the ketonic resin preswollen in trimethylorthoformate (TMOF)then the mixture is sonicated. Then, the borane pyridine complex (8M, 5to 10 eq.) is added and the mixture is agitated for 12 to 72 hours. Theresin is filtered, washed with solvents such as dichloromethane,dimethylformamide and tetrahydrofuran then dried under vacuum (Pelter,A.; Rosser, R. M. J. Chem. Soc. Perkin Trans I 1984, 717-720; Bomann, M.D.; Ouch, I. C.; DiMare, M. J. Org. Chem. 1995, 60, 5995-5996; Khan, N.M.; Arumugam, V.; Balasubramanian, S. Tetrahedron Lett. 1996, 37,4819-4822).

Preparation 3

300 mg (load rate of 0.88 mmol/g, 0.27 mmol) of ketonic resin ispreswollen in TMOF. Then 4-bromophenethylamine (540 mg, 420 μl, 2.7mmol, 10 eq.) then the borane pyridine complex (8 M, 338 μl, 2.7 mmol,10 eq.) are added. The mixture is agitated for 56 hours at ambienttemperature. The resin is filtered, rinsed successively withdichloromethane, dimethylformamide, tetrahydrofuran and dichloromethanethen dried under vacuum. 340 mg of pale yellow resin is thus obtainedwith a loud rate of 0.81 mmol/g calculated after elementary analysis ofthe nitrogen.

B3) Functionalization B3a) Functionalization with Isocyanates orIsothiocyanates

It is carried out according to the diagram

The general procedure is the following: the “secondary amine” resin ispreswollen in a solvent such as dichloromethane or dimethylformamidebefore the addition of isocyanate or isothiocyanate (3 to 10 eq.). Themixture is agitated for 1 to 24 hours at ambient temperature. The resinis then filtered, washed with solvents such as dichloromethane,dimethylformamide and tetrahydrofuran then dried under vacuum. Cleavageof the resin is carried out in the presence of an equimolar mixture ofdichloromethane and trifluoroacetic acid and agitation is carried outfor 30 minutes to 4 hours. The resin is rinsed with dichloromethane thenthe filtrate is concentrated under vacuum. In certain cases the filtrateis redissolved in dichloromethane then desalified with a saturatedsolution of sodium carbonate. The organic phase is evaporated undervacuum in order to produce the free base.

Example B3aN-(4-bromophenethyl)-N-(4-piperidinyl)-N′-[4-(trifluoromethyl)phenyl]urea(C₂₁H₂₃BrF₃N₃O, M=470.3)

55 mg (50 mmol) of resin (see Preparation 3) is preswollen in anhydrousdichloromethane. Then 4-trifluorophenylisocyanate (28 mg, 150 μmol, 3eq.) is added and the whole is agitated overnight. The resin isfiltered, rinsed with tetrahydrofuran, with dimethylformamide, withtetrahydrofuran then with dichloromethane before being dried undervacuum. Then agitation is carried out for 1.5 hour in the presence of800 μl of an equimolar mixture of dichloromethane and trifluoroaceticacid. The resin is filtered and rinsed with dichloromethane, thefiltrate is concentrated, rediluted in dichloromethane and washed with asaturated solution of sodium bicarbonate. 6 mg of a brown oil(yield=25%) is thus isolated.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.53 (m, 4H); 7.44 (d, J=6.8 Hz, 2H); 7.21(d, J=8.4 Hz, 2H); 4.1 (m, 1H); 3.53 (t, J=7.2 Hz, 2H); 3.12 (d, J=12.8Hz, 2H); 2.89 (t, J=8 Hz, 2H); 2.7 (m, 2H); 1.73 (m, 4H). MS/LC:m/z=472.2 (M+H).

A series of ureas (Y═O) and thioureas (Y═S) was synthesized according tothis procedure. The R₁ radicals which can be envisaged are thefollowing:

The X₁ radicals which can be envisaged are those illustrated in point Aabove.

B3b) Functionalization with Sulphonyl Chlorides

It is carried out according to the following diagram

General procedure: the “secondary amine” resin is preswollen in solventssuch as dichloromethane, dimethylformamide or tetrahydrofuran. Thensulphonyl chloride (5 to 10 eq.) and triethylamine (6 to 12 eq.) areadded and the mixture is agitated for 12 to 24 hours at ambienttemperature. The resin is filtered, washed with solvents such asdichloromethane, dimethylformamide and tetrahydrofuran, then dried undervacuum. Then the resin is agitated for 1 to 4 hours in the presence ofan equimolar mixture of dichloromethane and trifluoroacetic acid. Theresin is rinsed with dichloromethane then the filtrate is concentratedunder vacuum. In certain cases the filtrate is redissolved indichloromethane then desalified with a saturated solution of sodiumcarbonate. The organic phase is evaporated under vacuum in order toproduce the free base.

Example B3b N-(4-bromophenethyl)-4-methoxy-N-(4-piperidinyl)phenylsulphonamide (C₂₀H₂₅BrN₂O₃S, M=453.4)

55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydrousdichloromethane. Then triethylamine (42 μl, 300 μmol, 6 eq.) then4-methoxybenzene sulphonyl chloride (51.5 mg, 250 μmol, 5 eq.) are addedand the whole is agitated overnight. The resin is filtered, rinsed withtetrahydrofuran, with dimethylformamide, with tetrahydrofuran then withdichloromethane before being dried under vacuum. The reaction isrepeated a second time in order to have a complete substitution. 800 μlof an equimolar mixture of dichloromethane and trifluoroacetic acid isadded and agitation is carried out for 1.5 hour at ambient temperature.The resin is filtered and rinsed with dichloromethane. The filtrate isconcentrated, redilated in dichloromethane and washed with a saturatedsolution of sodium bicarbonate. 14 mg of a brown oil. (yield=63%) werethus isolated.

NMR ¹H(CD₃OD, 400 MHz) δ: 7.8 (dd, J=2.8 and 10 Hz, 2H); 7.44 (dd, J=1.2and 6.8 Hz, 2H); 7.17 (d, J=8.4 Hz, 2H); 7.07 (dd, J=3.2 and 10 Hz, 2H);3.87 (s, 3H, OCH₃); 3.72 (m, 1H); 3.3 (m, 2H); 3.04 (d, J=12.8 Hz, 2H);2.92 (t, J=8.4 Hz, 2H); 2.6 (t, J=12.4 Hz, 2H); 1.58 (m, 2H); 1.47(broad d, J=10 Hz, 2H). MS/LC: m/z=455 (M+H).

A series of sulphonamides was synthesized according to this procedure.The R₁ radicals which can be envisaged are those illustrated in points Aand B3a above. The X₃ radicals which can be envisaged are the following:

B3c) Functionalization with Acid Chlorides

It is carried out according to the following diagram

General procedure: the “secondary amine” resin is preswollen in solventssuch as dichloromethane, dimethylformamide or tetrahydrofuran. Then theacid chloride (5 to 10 eq.) and triethylamine (6 to 12 eq.) are addedand the mixture is agitated for 12 to 24 hours at ambient temperature.The resin is filtered, washed with solvents such as dichloromethane,dimethylformamide and tetrahydrofuran, then dried under vacuum. Theresin is then agitated for 1 to 4 hours in the presence of an equimolarmixture of dichloromethane and trifluoroacetic acid. The resin is rinsedwith dichloromethane then the filtrate is concentrated under vacuum. Incertain cases the filtrate is redissolved in dichloromethane thendesalified with a saturated solution of sodium carbonate. The organicphase is evaporated under vacuum in order to produce the free base.

Example B3c N-(4-bromophenethyl)-N-(4-piperidinyl)-2-thiophenecarboxamide (C₁₈H₂₁BrN₂OS, M=393.3)

55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydroustetrahydrofuran. Then triethylamine (42 μl, 300 μmol, 6 eq.) then2-thiophene carbonyl chloride (37 mg, 250 μmmol, 5 eq.) are added andthe whole is agitated overnight. The resin is filtered, rinsed withtetrahydrofuran, with dimethylformamide, with tetrahydrofuran then withdichloromethane before being dried under vacuum. 800 μl of an equimolarmixture of dichloromethane and trifluoroacetic acid is added andagitation is carried out for 1.5 hour at ambient temperature. The resinis filtered and rinsed with dichloromethane. The filtrate isconcentrated, rediluted in dichloromethane and washed with a saturatedsolution of sodium bicarbonate in order to obtain 10 mg of a brown oil(yield=50%).

NMR ¹H(CD₃OD, 400 MHz) δ: 7.64 (dd, J=0.8 and 4.8 Hz, 1H); 7.44 (d,J=8.4 Hz, 2H); 7.36 (d, J=3.6 Hz, 1H); 7.14 (m, 3H); 4.11 (m, 1H); 3.61(t, J=8 Hz, 2H); 3.09 (d, J=12 Hz, 2H); 2.92 (m, 2H); 2.54 (m, 2H); 1.82(m, 2H); 1.7 (m, 2H). MS/LC: m/z=393.1 (M+H).

A series of amides was synthesized according to this procedure. The R₁groups envisaged are those illustrated in points A and B3 above. The X₂groups are illustrated below.

B3d) Functionalization with Carboxylic Acids

It is carried out according to the procedure described in the literature(Kobayashi, S; Aoki, Y., J. Comb. Chem. 1999, 1, 371-372) following thediagram:

General procedure: the “secondary amine” resin is preswollen in solventssuch as dichloromethane, dimethylformamide or tetrahydrofuran. Then thecarboxylic acid (3 to 5 eq.), benzo-triazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBoP, 3 to 5 eq.) anddiisopropylethylamine (6 to 10 eq.) are added and the mixture isagitated for 24 hours at ambient temperature. The resin is filtered,washed with solvents such as dichloromethane, dimethylformamide andtetrahydrofuran, then dried under vacuum. Then the resin is agitated for1 to 4 hours in the presence of an equimolar mixture of dichloromethaneand trifluoroacetic acid. The resin is rinsed with dichloromethane thenthe filtrate is concentrated under vacuum. In certain cases the filtrateis redissolved in dichloromethane then desalified with a saturatedsolution of sodium carbonate. The organic phase is evaporated undervacuum in order to produce the free base.

Example B3d N-[2-(4-bromophenyl)ethyl]-N-(4-piperidinyl)acetamide(C₁₅H₂₁BrN₂O, M=325.25)

55 mg (50 μmol) of resin (see Preparation 3) is preswollen in anhydrousdimethylformamide. Then acetic acid (8.8 mg, 150 μmol, 3 eq.) PyBoP (76mg, 150 μmol, 3 eq.) then diisopropylethylamine (38 mg, 300 μmol, 6 eq.)are added and the whole is agitated overnight. The resin is filtered,rinsed with dimethylformamide, with tetrahydrofuran then withdichloromethane before being dried under vacuum. 800 μl of an equimolarmixture of dichloromethane and trifluoroacetic acid is added andagitation is carried out for 1.5 hour at ambient temperature. The resinis filtered and rinsed with dichloromethane. The filtrate isconcentrated, rediluted in dichloromethane and washed with a saturatedsolution of sodium bicarbonate in order to obtain 11 mg of a brown oil(yield=68%).

NMR ¹H (CD₃OD, 400 MHz) δ: 7.44 (m, 2H); 7.20 (m, 2H); 4.05 (m, 1H);3.45 (m, 2H); 3.10 (m, 2H); 2.83 (m, 2H); 2.64 (m, 2H); 2.13 (s, 3H);1.73 (m, 4H). MS/LC: m/z=325.2 (M+H).

A series of amides was synthesized according to this procedure. The R₁groups envisaged are those illustrated in points A and B3a above. The X₂groups are illustrated in point A above.

C) FUNCTIONALIZATION OF THE PIPERIDINE PART IN SOLUTION C1) Obtainingpiperidine with R₃═—C(Y)NHX₁

It is carried out according to the diagram

General procedure: an isocyanate or isothiocyanate (1.1 to 1.5 eq.) isadded to piperidine in the form of the free base diluted indichloromethane. The mixture is agitated for one to 18 hours at ambienttemperature. The aminomethyl resin (0.2 to 1 eq.) is added and themixture is again agitated for 2 to 18 hours. In certain cases, ionexchange resin such as IRA68 or SAX is added. The resins are filteredand the filtrate is concentrated. In certain cases, the product isdissolved in dichloromethane or ethyl acetate then filtered on a silicagel or basic alumina cartridge (500 mg, Interchim).

Example C14-((3,3-diphenylpropyl){[3-(trifluoromethyl)anilino]carbonyl}amino)-N-phenyl-1-piperidinecarboxamide (C₃₅H₃₅F₃N₄O₂, M=600.68)

N-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea(24 mg, 0.05 mmol) is dissolved in dichloromethane. Phenylisocyanate (9mg, 0.075 mmol, 1.5 eq.) is added and the mixture is agitated for 2.5hours. The aminomethyl resin (0.02 mmol) is added and the reaction isagain agitated overnight. The resin is filtered, rinsed withdichloromethane and the filtrate is concentrated. The oil obtained ispassed through a silica gel cartridge eluting with an equimolar mixtureof heptane and ethyl acetate in order to obtain 12 mg (yield=40%) of ayellow oil after concentration.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.72 (s, 1H); 7.58 (d, 1H); 7.44 (m, 1H);7.38 (m, 2H); 7.29 (m, 12H); 7.12 (m, 2H); 7.07 (m, 1H); 4.2 (d, J=12.4Hz, 3H); 3.21 (t, J=8 Hz, 2H); 2.9 (t, J=12.4 Hz, 2H); 2.38 (q, J=8 Hz,2H); 1.73 (d, J=10 Hz, 2H); 1.54 (qd, J=3.6 and 12 Hz, 2H). MS/LC:m/z=601.4 (M+H).

A series of ureas (Y═O) and thioureas (Y═S) was synthesized according tothis procedure. The R₁, X₁ and X₂ groups which can be envisaged, arethose illustrated in the above points (A and B3a), A, and (A and B3c)respectively.

C2) Functionalization with Carboxylic Acids

It is carried out according to the following diagram

General procedure: the P-EDC resin (1.3 to 3 eq.) is preswollen inanhydrous dichloromethane. Carboxylic acid (1.1 to 2.5 eq.) is dissolvedin an anhydrous solvent such as dichloromethane, dimethylformamide ortetrahydrofuran and is added to the resin. This mixture is agitated for5 to 30 minutes at ambient temperature. The 4-aminodisubstitutedpiperidine, in the form of the free base, in solution in an anhydroussolvent such as dichloromethane, dimethylformamide or tetrahydrofuran isthen added to this mixture and the whole is agitated for 1 to 18 hoursat ambient temperature. In certain cases, ion exchange resin such asIRA68 or SAX is added and the mixture is again agitated at ambienttemperature for 1 to 18 hours. The resins are filtered on frit, on a SAXion exchange resin cartridge (500 mg, Interchim) or on a basic aluminacartridge (500 mg, Interchim).

Example C2N-(1-acetyl-4-piperidinyl)-N-(3,3-diphenylpropyl)-N′-[3-(trifluoromethyl)phenyl]urea(C₃₀H₃₂F₃N₃O₂, M=523.60)

117 mg (175 μmol, 3.5 eq.) of P-EDC resin is preswollen in 1.5 ml ofanhydrous dichloromethane. Acetic acid (7.5 mg, 125 μmol, 2.5 eq.) isadded and the mixture is agitated for 10 minutes. ThenN-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea(24.3 mg, 50 μmol) is added in its turn and the mixture is agitatedovernight. The resin is filtered and the filtrate is concentrated. Theoil obtained is passed through a silica gel cartridge eluting with anequimolar mixture of heptane and ethyl acetate in order to obtain 16 mg(yield=62%) of a white foam after concentration.

NMR ¹H (CD₃OD, 400 MHz) δ: 7.71 (s, 1H); 7.58 (d, J=8.4 Hz, 1H); 7.43(t, J=8 Hz, 1H); 7.28 (m, 9H); 7.17 (m, 2H); 4.56 (dd, J=2 and 11.2 Hz,1H); 4.17 (m, 1H); 3.96 (t, J=7.6 Hz, 1H); 3.88 (d, J=12 Hz, 1H); 3.19(q, J=4 and 8 Hz, 2H); 3.1 (t, 12 Hz, 1H); 2.58 (t, J=12 Hz, 1H); 2.37(m, 2H); 2.06 (s, 3H, CH₃); 1.72 (t, J=14.4 Hz, 2H); 1.43 (qd, J=4 and12.4 Hz, 2H). MS/LC: m/z=524.3 (M+H).

A series of amides was synthesized according to this procedure. The R₁,X₁ and X₂ groups which can be envisaged, are those illustrated in points(A and B3a), A, (A and B3c) respectively.

C3) Functionalization with Sulphonyl Chlorides

It is carried out according to the following diagram

General procedure: the morpholinomethyl resin (Novabiochem, 2 to 3 eq.)is preswollen in anhydrous solvents such as dichloromethane,dimethylformamide or tetrahydrofuran. Sulphonyl chloride (1.1 to 2 eq.)dissolved in anhydrous solvents such as dichloromethane,dimethylformamide or tetrahydrofuran is added, followed by4-aminodisubstituted piperidine. The mixture is agitated for 16 to 48hours. The aminomethyl resin (0.1 to 1.5 eq.) is added and the reactionmedium is agitated overnight. In certain cases, ion exchange resin suchas IRA68 or SAX is added and the mixture is agitated at ambienttemperature for 1 to 18 hours. The resins are filtered on frit, on a SAXion exchange resin cartridge (500 mg, Interchim) or on a basic aluminacartridge (500 mg, Interchim).

Example C3N-(3,3-diphenylpropyl)-N-{1-[(4-methoxyphenyl)sulphonyl]-4-piperidinyl}-N′-[′-(trifluoromethyl)phenyl]urea(C₃₅H₃₆F₃N₃O₄S, M=651.75)

27.5 mg (100 μmol, 2 eq.) of morpholinomethyl resin is preswollen inanhydrous tetrahydrofuran, then 4-methoxyphenylsulphonyl chloride (15.5mg, 0.075 mmol, 1.5 eq.) thenN-(3,3-diphenylpropyl)-N-(4-piperidinyl)-N′-[3-(trifluoromethyl)phenyl]urea(24.3 mg, 0.05 mmol) are added. The mixture is agitated overnight. Theaminomethyl (20 mg) and SAX ion exchange resins are added and themixture is agitated overnight. The resins are filtered and rinsed withdichloromethane. The oil obtained after evaporation is passed through asilica gel cartridge (500 mg, Interchim) eluting with ethyl acetate inorder to obtain 18 mg (yield=56%) of a white solid after concentration.

NMR ¹H(CD₃OD, 400 MHz) δ: 7.71 (d, J=9.2 Hz, 2H); 7.65 (s, 1H); 7.51 (d,1H); 7.41 (t, J=7.6 Hz, 1H); 7.29 (m, 9H); 7.20 (m, 2H); 7.11 (dd, J=1.6and 6.8 Hz, 2H); 3.88 (s, 3H, OCH₃); 3.77 (d, J=12.4 Hz, 2H); 3.16 (t.J=8 Hz, 2H); 2.33 (m, 4H): 1.71 (d. J=10 Hz, 2H); 1.62 (qd, J=4 and 12Hz, 2H); 1.3 (m, 2H). MS/LC: m/z=652.4 (M+H).

A series of sulphonamides was synthesized according to this procedure.The R₁, X₁, X₂ and X₃ groups which can be envisaged are thoseillustrated in points (A and B3a), A, (A and B3c) and B3b respectively.

D) SYNTHESIS OF TRI-substituted PIPERIDINES IN SOLID PHASE

It is carried out starting from vinyl sulphone resin (Kroll, F. E. K.;Morphy, R.; Rees, D.; Gani, D. Tetrahedron Lett. 1997, 38, 8573-8576.;Brown, A. R. J. Comb. Chem. 1999, 1, 283-285) according to the followingdiagram:

D1) Preparation of the Resin

It is carried out according to the following diagram:

Triethylamine (1 eq.) is added to hydrated piperidone hydrochloridediluted in dimethylformamide. The mixture is heated until completedissolution of the ketone. This solution is added to the vinyl sulphoneresin (0.05 eq.) preswollen in dimethylformamide. After agitation for 24to 72 hours at ambient temperature, the resin is filtered then washedseveral times with dimethylformamide, tetrahydrofuran, diethylether anddichloromethane.

Preparation 4

1.5 g of vinyl sulphone resin (Novabiochem, load rate of 1 mmol/g, 1.5mmol) is preswollen in 50 ml of dimethylformamide. At the same time, 2.3g (15 mmol, 10 eq.) of hydrated piperidone hydrochloride and 1.8 g (15mmol, 10 eq.) of triethylamine are heated in 100 ml of dimethylformamideuntil complete dissolution. The yellowish solution is poured warm ontothe resin and the mixture is agitated for 24 hours at ambienttemperature. The resin is filtered then washed with dimethylformamide,tetrahydrofuran, diethylether and dichloromethane (3 times with eachsolvent) then dried under vacuum. 1.7 g of pale yellow resin is isolatedwith a load rate of 1 mmol/g calculated after elementary analysis of thenitrogen.

D2) Reducing Amination on Solid Support

It is carried out according to the procedure described in the literature(Pelter, A.; Rosser, R. M.; J. Chem. Soc. Perkin Trans I 1984, 717-720;Bomann, M. D.; Guch. I. C.; DiMare, M.; J. Org. Chem. 1995, 60,5995-5996; Khan, N. M.; Arumugam, V.; Balasubramanian, S.; TetrahedronLett. 1996, 37, 4819-4822) following the diagram:

General procedure: The primary amine (5 to 10 eq.) is added to theketonic resin preswollen in trimethylorthoformate (TMOF) then themixture is sonicated. Then the borane pyridine complex (8 M, 5 to 10eq.) is added and the mixture is agitated for 12 to 72 hours. The resinis filtered, washed with solvents such as dichloromethane,dimethylformamide, methanol and tetrahydrofuran then dried under vacuum.

Preparation 5

1 g (load rate of 1 mmol/g, 1 mmol) of ketonic resin is preswollen inTMOF. Then 2-(1-methyl-1H-indol-3-yl)ethylamine (1.01 g, 10 mmol, 10eq.) then the borane pyridine complex (8M, 1.25 ml, 10 mmol, 10 eq.) areadded. The mixture is agitated for 48 hours at ambient temperature. Theresin is filtered, rinsed successively with dichloromethane,dimethylformamide, methanol, tetrahydrofuran and dichloromethane thendried under vacuum. 1.05 g of pale yellow resin is thus obtained with aload rate of 0.91 mmol/g calculated after elementary analysis of thenitrogen.

D3) Functionalization of the Secondary Amine D3a) Functionalization withIsocyanates

General procedure: the “secondary amine” resin is preswollen in asolvent such as dichloromethane or dimethylformamide before the additionof isocyanate (3 to 10 eq.). The mixture is agitated for 1 to 24 hoursat ambient temperature. The resin is then filtered, washed with solventssuch as dichloromethane, dimethylformamide and tetrahydrofuran thendried under vacuum.

Preparation 6

55 mg (50 μmol) of resin (see Preparation 5) is preswollen in anhydrousdichloromethane. Then 4-trifluorophenylisocyanate (28 mg, 150 μmol, 3eq.) is added and the whole is agitated for 2 hours at ambienttemperature. The resin is filtered, rinsed with tetrahydrofuran, withdimethylformamide, with tetrahydrofuran then with dichloromethane beforebeing dried under vacuum.

D3b) Functionalization with Sulphonyl Chlorides

The functionalization operating method is identical to that stated inpoint B3b.

D3c) Functionalization with Acid Chlorides

The functionalization operating method is identical to that stated inpoint B3c.

D3d) Functionalization with Carboxylic Acids

The functionalization operating method is identical to that stated inpoint B3d.

D4) Cleavage Stage

The cleavage stage described below is valid whatever thefunctionalization carried out beforehand on the secondary amine:

General procedure: The disubstituted resin is swollen in solvents suchas dichloromethane, dimethylformamide or tetrahydrofuran then the halideR₃X is added in which R₃ has the meaning indicated previously and Xrepresents a halogen atom (5 eq.) and the mixture agitated overnight ata temperature comprised between 20 and 60° C. The resin is filtered,rinsed with solvents such as dimethylformamide, tetrahydrofuran,methanol and dichloromethane then dried under vacuum. The resin isswollen again in dichloromethane and basic ion exchange resin (Ouyang,X.; Armstrong, R. W.; Murphy, M. M. J. Org. Chem. 1998, 63, 1027-1032)is added. The whole is agitated for 48 hours at ambient temperature. Theresins are filtered, rinsed with dichloromethane and the filtrate isconcentrated under vacuum.

Example D4N-[2-(1-methyl-1H-indol-3-yl)ethyl]-N-(1-methyl-4-piperidinyl)-N′-[4-(trifluoromethyl)phenyl]urea(C₂₅H₂₉F₃N₄O, M=458.5)

55 mg (50 μmol) of the urea resin is swollen in dimethylformamide then35 mg (250 μmol, 5 eq.) of iodomethane is added and the mixture isagitated for 18 hours at ambient temperature. The resin is filtered,rinsed with dimethylformamide, tetrahydrofuran, methanol anddichloromethane then dried under vacuum. The resin is swollen again indichloromethane then approximately 100 mg of amberlite IRA68 resin isadded and the mixture is agitated for 48 hours. The resins are filtered,rinsed with dichloromethane and the filtrate is concentrated in order toproduce 18 mg (yield=78%) of a colourless oil.

NMR ¹H(CD₃OD, 400 MHz) δ: 7.65 (m, 2H); 7.40 (m, 2H); 7.31 (m, 1H); 7.20(t, 1H); 7.10 (m, 1H); 7.06 (m, 2H); 4.04 (m, 1H); 3.68 (s, 3H); 3.60(t, 2H); 3.04 (t, 2H); 2.94 (m, 2H); 2.29 (s, 3H); 2.14 (m, 2H); 1.91(m, 2H); 1.76 (m, 2H). MS/LC: m/z=459.3 (M+H).

For the R₁, X₁, X₂ and X₃ groups as illustrated in points A and B above,the R₃ groups which can be envisaged for the synthesis of trisubstituted4-aminopiperidines according to the above procedure, are the following:

A subject of the invention is also the process for the preparation ofcompounds I according to the invention, in solid or liquid phase, asdescribed previously.

A more particular subject of the invention is a process for thepreparation, in liquid phase, of compounds of formula I as definedabove, characterized in that it comprises the reducing amination of thefollowing N-substituted piperidone

-   in which R represents the methyl or Boc radical, in the presence of    an amine of formula R₁NH₂ in which R₁ has the meaning indicated    above, in order to obtain the compound of formula 1

-   which compound of formula (1) is reacted with-   A) either a compound of formula X₁NC(Y) in which X₁ and Y have the    meaning indicated above, in order to obtain a compound of formula    (2)

-   which compound of formula (2) represents the corresponding compound    of formula (I) in which R₃ represents Me or Boc and which, when R₃    represents Boc, can be subjected to an acid treatment in order to    obtain the corresponding compound of formula (I) in which R₃    represents the hydrogen atom,-   which compound of formula (I) thus obtained can be reacted with a    compound of formula X₁NC(Y), X₂CO₂H or X₃SO₂Cl in which X₁, Y, X₂    and X₃ have the meaning indicated above, in order to obtain the    corresponding compound of formula I in which R₂ represents a radical    of formula —C(Y)NHX₁ and R₃ the —C(Y)—NHX₁, —C(O)X₂ or SO₂X₃ radical    respectively;-   B) or a compound of formula X₂CO₂H in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (3)

-   which compound of formula (3) represents the corresponding compound    of formula (I) in which R₃ represents Me or Boc and which, when R₃    represents Boc, can be subjected to an acid treatment in order to    obtain the corresponding compound of formula (I) in which R₃    represents the hydrogen atom,-   which compound of formula (I) thus obtained can be reacted with a    compound of formula X₁NC(Y), X₂CO₂H or X₃SO₂Cl in which X₁, Y, X₂    and X₃ have the meaning indicated above, in order to obtain the    corresponding compound of formula I in which R₂ represents a radical    of formula —C(O)X₂ and R₃ the —C(Y)—NHX₁, —C(O)X₂ or SO₂X₃ radical    respectively.

A more particular subject of the invention is also a preparationprocess, in solid phase, for compounds of formula I as defined above,characterized in that it comprises

-   the reducing amination of the ketonic resin

-   in the presence of an amine of formula R₁NH₂ in which R₁ has the    meaning indicated above, in order to obtain the compound of formula    (4)

-   which compound of formula (4) is reacted with-   A) either a compound of formula X₁NC(Y) in which X₁ and Y have the    meaning indicated above, in order to obtain a compound of formula    (5)

-   followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I) in which R₃ represents the    hydrogen atom.-   B) or a compound of formula X₃SO₂Cl in which X₃ has the meaning    indicated above, in order to obtain a compound of formula (6)

-   followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I) in which R₃ represents the    hydrogen atom,-   C) or a compound of formula X₂CO₂Cl in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (7)

-   followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I) in which R₃ represents the    hydrogen atom;-   D) or a compound of formula X₂CO₂H in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (7) as    defined above, followed by cleavage of the resin in order to obtain    the corresponding compound of formula (I) in which R₃ represents the    hydrogen atom.

Finally a more particular subject of the invention is a preparationprocess, in solid phase, for compounds of formula I as defined above,characterized in that it comprises

-   the reducing amination of the ketonic resin

-   in the presence of an amine of formula R₁NH₂ in which R₁ has the    meaning indicated above, in order to obtain the compound of formula    (8)

-   which compound of formula (8) is reacted with-   A) either a compound of formula X₁NC(O) in which X₁ has the meaning    indicated above; in order to obtain a compound of formula (9)

-   which compound (9) thus formed is reacted with a compound of formula    R₃X in which R₃ is as defined above and X represents Br or I,    followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I);-   B) or a compound of formula X₃SO₂Cl in which X₃ has the meaning    indicated above, in order to obtain a compound of formula (10)

-   which compound (10) thus formed is reacted with a compound of    formula R₃X in which R₃ is as defined above and X represents Br or    I, followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I);-   C) or a compound of formula X₂CO₂Cl in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (11)

-   which compound (11) thus formed is reacted with a compound of    formula R₃X in which R₃ is as defined above and X represents Br or    I, followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I);-   D) or a compound of formula X₂CO₂H in which X₂ has the meaning    indicated above, in order to obtain a compound of formula (11) as    defined above,-   which compound (11) thus formed is reacted with a compound of    formula R₃X in which R₃ is as defined above and X represents Br or    I, followed by cleavage of the resin in order to obtain the    corresponding compound of formula (I).

Compounds I of the present invention have useful pharmacologicalproperties. Thus it has been discovered that compounds I of the presentinvention have a high affinity for one (or more) of the somatostatinreceptors. They can be used as non-peptide agonists or antagonists ofsomatostatin in a selective or non-selective manner.

The compounds of the present invention can therefore be used indifferent therapeutic applications. They can advantageously be used totreat the pathological states or the diseases as presented above and inwhich one (or more) of the somatostatin receptors are involved.

An illustration of the pharmacological properties of the compounds ofthe invention will be found hereafter in the experimental part.

A subject of the present Application is also, as medicaments, theproducts of formula I as defined above, as well as the addition saltswith pharmaceutically acceptable mineral or organic acids of saidproducts of formula I, as well as the pharmaceutical compositionscontaining, as active ingredient, at least one of the medicaments asdefined above, in combination with a pharmaceutically acceptablesupport.

The pharmaceutical composition can be in the form of a solid, forexample, powders, granules, tablets, gelatin capsules or suppositories.Appropriate solid supports can be, for example, calcium phosphate,magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin,cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

The pharmaceutical compositions containing a compound of the inventioncan also be presented in liquid form, for example, solutions, emulsions,suspensions or syrups. Appropriate liquid supports can be, for example,water, organic solvents such as glycerol or glycols, similarly theirmixtures, in varying proportions, in water, with added pharmaceuticallyacceptable oils or fats. The sterile liquid compositions can be used forintramuscular, intraperitoneal or subcutaneous injections and thesterile compositions can also be administered intravenously.

Some compounds of the general formula I as defined above, are covered bythe patent application DE 2751138. This DE patent application describedcompounds which antagonise the effects of dopamine and endogenous orexogenous dopaminergic agents, and stimulate serotoninergic mechanism,activity which is far different from the activity of the compounds ofthe present invention.

A subject of the present invention is also the use of compounds ofgeneral formula I_(a)

in racemic, enantiomeric form or all combinations of these forms, inwhich:

-   R_(1a) represents a linear or branched (C₁-C₁₆)alkyl, alkenyl,    alkynyl, —(CH₂)_(m)—Y—Z₁₁ or —(CH₂)_(m)—Z₁₂ radical in which    -   Z₁₁ represents a (C₁-C₆)alkyl or aryl optionally substituted.    -   Z₁₂ represents cyano, cyclohexenyl, bis-phenyl,        (C₃-C₇)cycloalkyl, optionally substituted (C₃-C₇)        heterocycloalkyl, optionally substituted aryl or optionally        substituted heteroaryl,    -   or Z₁₂ represents a radical of formula

-   or R_(1a) represents a radical of formula

-   R_(2a) represents a radical of formula —C(Y)NHX₁, —C(O)X₂ or SO₂X₃;-   R_(3a) represents the hydrogen atom, an optionally substituted    alkyl, alkenyl, alkynyl, optionally substituted aralkyl, optionally    substituted heteroarylalkyl radical, or a radical of formula    —C(Y)—NHX₁, —(CH₂)_(n)—C(O)X₂, SO₂X₃ or

-   X₁ represents a linear or branched (C₁-C₁₅)alkyl, alkenyl, alkynyl,    —(CH₂)_(m)—Y—Z₂₁ or —(CH₂)_(p)Z₂₂ radical in which    -   Z₂₁ represents a (C₁-C₆)alkyl    -   Z₂₂ represents cyclohexenyl, indanyl, bis-phenyl,        (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, mono- or        di-alkylamino, —C(O)—O-alkyl, or aryl or heteroaryl optionally        substituted,    -   or Z₂₂ represents a radical of formula

-   X₂ represents a linear or branched (C₁-C₁₀)alkyl radical, an alkenyl    radical optionally substituted by a phenyl radical (the phenyl    radical being itself optionally substituted), an alkynyl radical, or    a radical of formula —(CH₂)_(m)—W—(CH₂)_(q)—Z₂₃ or —(CH₂)_(p)—U—Z₂₄    in which    -   Z₂₃ represents a (C₁-C₆)alkyl or aryl optionally substituted;    -   Z₂₄ represents alkyl, cyclohexenyl, bis-phenyl,        (C₃-C₇)cycloalkyl optionally substituted,        (C₃-C₇)heterocycloalkyl, cyano, amino, mono or di-alkylamino, or        aryl or heteroaryl optionally substituted,    -   or Z₂₄ represents a radical of formula

-   or X₂ represents a radical represented below:

-   where the protective group (PG) represents H or    tert-butyloxycarbonyl;-   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, an alkenyl    radical optionally substituted by a phenyl radical (the phenyl    radical being itself optionally substituted), CF₃, or —(CH₂)_(p)Z₂₅    in which    -   Z₂₅ represents aryl or heteroaryl optionally substituted,-   or X₃ represents a radical of formula

optionally substituted by one or more halo radicals identical ordifferent;

-   Y represents an oxygen or sulphur atom;-   W represents an oxygen or sulphur atom, or SO₂;-   U represents a covalent bond or the oxygen atom;-   n is an integer from 0 to 4;-   m is an integer from 1 to 6;-   p is an integer from 0 to 6;-   q is an integer from 0 to 2,    or their addition salts with pharmaceutically acceptable mineral or    organic acids, for the preparation of a medicament intended to treat    pathological states or diseases in which one (or more) receptor(s)    of somatostatin is (are) involved.

A more particularly subject of the invention is the use of products ofgeneral formula I_(a) as defined above, characterized in that

-   i) the substituent or substituents which can be carried by the aryl    radicals represented by Z₁₁ and Z₁₂ and heteroaryl represented by    Z₁₂ are chosen independently from the fluoro, chloro, bromo, iodo,    alkyl, alkoxy, alkylthio, —CF₃, —OCF₃, phenyl, phenoxy,    aminosulphonyl radicals;-   ii) the substituent or substituents which can be carried by the    heterocycloalkyl radical represented by Z₁₂ are chosen independently    from the oxy and alkyl radicals;-   iii) the substituent or substituents which can be carried by the    aryl and heteroaryl radicals represented by Z₂₂ are chosen    independently from the fluoro, chloro, bromo, iodo, alkyl, alkenyl,    alkoxy, alkylthio, CF₃, OCF₃, nitro, cyano, azido, aminosulphonyl,    piperidinosulphonyl, mono or di-alkylamino, —C(O)—O-alkyl,    —C(O)-alkyl, or phenyl, phenoxy, phenylthio, benzyloxy radicals, the    phenyl radical being able to be substituted;-   iv) the substituent or substituents which can be carried by the aryl    radicals represented by Z₂₃ and Z₂₄, cycloalkyl and heteroaryl    represented by Z₂₄ are chosen independently from the fluoro, chloro,    bromo, iodo, alkyl, alkoxy, alkylthio, CF₃, OCF₃, OCHF₂, SCF₃,    nitro, cyano, azido, hydroxy, —C(O)O-alkyl, —O—C(O)-alkyl,    —NH—C(O)-alkyl, alkylsulphonyl, mono- or di-alkylamino, amino,    aminoalkyl, pyrrolyl, pyrrolydinyl or the radicals phenyl, phenoxy,    phenylthio, benzyl, benzyloxy radicals the aryl radical of which is    optionally substituted by one or more alkyl, CF₃ or halo radicals;-   v) the substituent or substituents which can be carried by the aryl    and heteroaryl radicals represented by Z₂₅ are chosen independently    from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, OCF₃,    nitro, cyano, —NH—C(O)-alkyl, alkylsulphonyl, amino, mono- and    di-alkylamino, phenyl, pyridino radicals;-   vi) the substituent which can be carried by the alkyl radical    represented by R₃ is the cyano radical.-   vii) the substituent or substituents which can be carried by the    aralkyl radical represented by R₃ are chosen independently from the    fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, OCF₃, OCHF₂, SCF₃,    SCHF₂, nitro, cyano, —C(O)O-alkyl, alkylsulphonyl, thiadiazolyl    radicals, or the phenyl and phenoxy radicals the phenyl radical of    which is optionally substituted by one or more halo radicals.-   viii) the substituent or substituents which can be carried by the    heteroarylalkyl radical represented by R₃ are chosen independently    from the fluoro, chloro, bromo or nitro radicals.

A more particular subject of the present invention is the use ofcompounds of general formula I_(a) as defined above in which R_(1a)represents a linear or branched (C₁-C₆)alkyl radical, the—(CH₂)_(m)—Y—Z₁₁ or —(CH₂)_(m)—Z₁₂ radical in which

-   -   Z₁₁ represents a (C₁-C₆)alkyl,    -   Z₁₂ represents bis-phenyl, (C₃-C₇)cycloalkyl,        (C₃-C₇)heterocycloalkyl optionally substituted, or aryl or        heteroaryl optionally substituted by one or more substituents        chosen independently from the fluoro, chloro, bromo, iodo,        alkyl, alkoxy radicals,    -   or Z₁₂ represents

-   -   Y represents the oxygen atom,

-   or R_(1a) represents a radical of formula

A more particular subject of the present invention is the use ofcompounds of general formula I_(a) as defined above in which R_(2a)represents a radical of formula —C(Y)NHX₁, —C(O)X₂ or SO₂X₃ in which

-   -   X₁ represents a linear or branched (C₁-C₁₅)alkyl radical, or        —(CH₂)_(p)Z₂₂ in which        -   Z₂₂ represents cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl,            (C₃-C₇)heterocycloalkyl, mono- or di-alkylamino,            —C(O)—O-alkyl, or aryl or heteroaryl optionally substituted            by one or more radicals chosen independently from the            fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF₃,            OCF₃, nitro, cyano, azido, piperidinosulphonyl,            —C(O)—O-alkyl, —C(O)-alkyl, or phenyl radicals,        -   or Z₂₂ represents a radical of formula

-   -   X₂ represents a linear or branched (C₁-C₁₀)alkyl, alkynyl,        —(CH₂)_(m)—W—(CH₂)_(q)—Z₂₃ or —(CH₂)_(p)—U—Z₂₄ radical in which        -   W represents SO₂,        -   U represents a covalent bond,        -   Z₂₃ represents an aryl radical;        -   Z₂₄ represents cyclohexenyl, bis-phenyl, (C₃-C₇)cycloalkyl            optionally substituted by an aminoalkyl, or aryl or            heteroaryl radical optionally substituted by one or more            radicals chosen from fluoro, chloro, bromo, iodo, alkyl,            alkoxy, —CF₃, —OCF₃, SCF₃, hydroxy, —O—C(O)-alkyl, mono- or            di-alkylamino, amino        -   or Z₂₄ represents a radical of formula

-   -   or X₂ represents

-   -   X₃ represents a —(CH₂)_(p)Z₂₅ radical in which Z₂₅ represents an        aryl radical optionally substituted by one or more identical or        different radicals chosen from alkoxy and CF₃.

A more particular subject of the present invention is the use ofcompounds of general formula I_(a) as defined above in which R_(3a)represents the hydrogen atom, an alkyl, alkenyl, heteroarylalkyl radicaloptionally substituted or a radical of formula —C(Y)—NHX₁, —C(O)X₂, orSO₂X₃ in which

-   -   X₁ represents a —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents an aryl radical optionally substituted by one            or more radicals chosen independently from the fluoro,            chloro, bromo, iodo, alkyl, alkoxy, CF₃, nitro, phenoxy            radicals;    -   X₂ represents the vinyl radical substituted by a phenyl, the        phenyl radical being itself optionally substituted by one or        more halo, or —(CH₂)_(p)—U—Z₂₄ radicals in which        -   Z₂₃ represents alkyl, (C₃-C₇)cycloalkyl,            (C₃-C₇)heterocycloalkyl, bis-phenyl, amino, mono or            di-alkylamino, or aryl or heteroaryl optionally substituted            by one or more radicals chosen from alkoxy, bromo, chloro,            fluoro, hydroxy, CF₃, nitro, amino, mono- and di-alkylamino            pyrrolyl,    -   or X₂ represents a radical of formula

-   -   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, the        vinyl radical substituted by a radical (the phenyl radical being        itself optionally substituted), CF₃, or —(CH₂)_(p)Z₂₅ in which        -   Z₂₅ represents aryl or heteroaryl optionally substituted by            one or more substituents chosen independently from the            fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃, nitro,            —NH—C(O)-alkyl, mono- and di-alkylamino radicals.

Preferentially, R_(1a) represents a linear or branched (C₁-C₆)alkylradical, the —(CH₂)_(m)—Y—Z₁₁ or —(CH₂)_(m)—Z₁₂ radical in which

-   -   Z₁₁ represents a (C₁-C₆)alkyl,    -   Z₁₂ represents naphthyl, morpholino, bis-phenyl, pyrrolidinyl        substituted by the oxy radical, or the phenyl, piperazinyl,        pyridinyl and indolyl radicals which are optionally substituted        by one or more substituents chosen independently from the bromo,        fluoro, chloro, alkyl, alkoxy, —CF₃, —OCF₃ radicals;    -   or Z₁₂ represents

-   -   Y represents the oxygen atom,

-   or R_(1a) represents a radical of formula given below:

Preferentially, R_(2a) represents a radical of formula —C(Y)NHX₁,—C(O)X₂ or SO₂X₃ in which

-   -   X₁ represents a linear or branched (C₁-C₁₀)alkyl, or        —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents cyclohexyl, cyclohexenyl, bis-phenyl,            morpholino, piperidino, mono- or di-alkylamino,            —C(O)—O-alkyl, or phenyl, naphthyl or furyl optionally            substituted by one or more radicals chosen independently            from the fluoro, chloro, bromo, iodo, alkyl, alkoxy,            alkylthio, CF₃, OCF₃, nitro, cyano, azido,            piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl            radicals,        -   or Z₂₂ represents a radical of formula

-   -   X₂ represents an alkyl, alkynyl, —(CH₂)_(m)—W—(CH₂)_(q)—Z₂₃ or        —(CH₂)_(p)Z₂₄ radical in which        -   W represents SO₂;        -   Z₂₃ represents the phenyl radical;        -   Z₂₄ represents cyclohexenyl, bis-phenyl, cyclohexyl            optionally substituted by an aminoalkyl, or phenyl,            naphthyl, benzothienyl, thienyl or indolyl radical            optionally substituted by one or more radicals chosen from            fluoro, chloro, bromo, iodo, alkyl, alkoxy, —CF₃, —OCF₃,            SCF₃, hydroxy, —O—C(O)-alkyl, —NH—C(O)-alkyl, mono- or            di-alkylamino, amino, or        -   Z₂₄ represents a radical of formula

-   -   or X₂ represents

-   -   X₃ represents a —(CH₂)_(p)Z₂₅ radical in which Z₂₅ represents        the phenyl radical optionally substituted by one or more        identical or different radicals chosen from alkoxy and CF₃,

Preferentially, R_(3a) represents the hydrogen atom, an alkyl, alkenylor furyl-methyl radical substituted by one or more nitro radicals, or aradical of formula —C(Y)—NHX₁, —C(O)X₂ or SO₂X₃ in which

-   -   X₁ represents a —(CH₂)_(p)Z₂₂ radical in which        -   Z₂₂ represents the phenyl or naphthyl radical optionally            substituted by one or more radicals chosen independently            from the fluoro, chloro, bromo, iodo, alkyl, alkoxy, CF₃,            nitro, phenoxy radicals,    -   X₂ represents the vinyl radical substituted by a phenyl radical        itself optionally substituted by one or more halo, or        —(CH₂)_(p)—U—Z₂₄ radicals in which        -   Z₂₄ represents alkyl, cyclohexyl, tetrahydrofuryl,            bis-phenyl, amino, mono or di-alkylamino, or phenyl,            indolyl, thienyl, pyridinyl, benzothienyl and furyl            optionally substituted by one or more radicals chosen from            alkoxy, bromo, chloro, fluoro, amino, mono- and            di-alkylamino, nitro, hydroxy, pyrrolyl    -   or X₂ represents a radical of formula

-   -   X₃ represents a linear or branched (C₁-C₁₀)alkyl radical, the        vinyl radical substituted by a phenyl, CF₃, or —(CH₂)_(p)Z₂₅        radical in which        -   Z₂₅ represents a phenyl, naphtyl, thienyl, pyrazolyl or            thiazolyl radical optionally substituted by one or more            substituents chosen independently from the fluoro, chloro,            bromo, iodo, alkyl, alkoxy, CF₃, nitro, —NH—C(O)-alkyl,            mono- and di-alkylamino radicals;

Very preferentially, R_(1a) represents the —(CH₂)_(m)Z₁₂ radical inwhich m=2 and Z₁₂ represents bis-phenyl or the radical indolylsubstituted by one or more substituents chosen independently from thealkyl and alkoxy radicals.

Very preferentially, R_(2a) represents the radicals of formula —C(Y)NHX₁and —C(O)X₂ in which

-   -   Y represents S;    -   X₁ represents a phenyl radical optionally substituted by one or        more azido radicals,    -   X₂ represents —(CH₂)_(p)Z₂₄ in which        -   p is equal to 1, 2 or 3,        -   Z₂₄ represents cyclohexyl, or phenyl or benzothienyl            optionally substituted by one or more radicals chosen from            fluoro, chloro, bromo, iodo or —CF₃.

Very preferentially, R_(3a) represents the hydrogen atom or the methylradical.

All the technical and scientific terms used in the present text have themeaning known to a person skilled in the art. Furthermore, all patents(or patent applications) as well as other bibliographical references areincorporated by way of reference.

Experimental Part

Other compounds according to the invention obtained according to theprocedures of Examples A, B, C and D described previously, are set outin the table below.

The compounds are characterized by their retention time (rt), expressedin minutes, and their molecular peak (M+H+) determined by massspectroscopy (MS).

For the mass spectroscopy, a single quadripole mass spectrometer(Micromass, Platform model) equipped with an electrospray source is usedwith a resolution of 0.8 Da at 50% valley. The conditions for Examples 1to 778 below, are as follows:

Conditions C1 and C2

Eluent: A: Water+0.02% trifluoracetic acid; B: acetonitrile

T (min) A % B % 0 100 0 1 100 0 10 15 85 12 15 85

Condition C1 Condition C2 Flow rate: 1.1 ml/min Flow rate: 1.1 ml/minInjection: 5 μl Injection: 20 μl Temp: 40° C. Temp: 40° C. Wavelength (%UV): 210 nm Wavelength (% UV): 210 nm Column: Uptisphere ODS 3 μmColumn: Kromasyl ODS 3.5 μm 33 * 4.6 mm i.d 50 * 4.6 mm i.dConditions C3

Eluent: A: Water+0.02% trifluoracetic acid; B: acetonitrile

T (min) A % B % 0 90 10 6 15 85 10 15 85

-   Flow rate: 1 ml/min-   Injection 5 μl-   Column: Uptisphere ODS 3 μm 50*4.6 mm i.d-   Temp: 40° C.-   Wavelength (% UV): 220 nm

The conditions depending on the examples, are as follows:

Examples Conditions  1 to 29 C2  30 to 263 C1 264 to 425 C3 426 to 456C2 457 to 503 C3 504 to 586 C1 587 to 778 C3

These examples are presented to illustrate the above procedures andshould in no way be considered as limiting the scope of the invention.

Purity M + Ex R₁ R₂ R₃ (%) rt H+  1

66 7.6 523.3  2 ″ ″

94 7.7 543.2  3 ″ ″

96 8.1 557.2  4 ″ ″

98 8.5 593.2  5 ″ ″

95 7.8 557.2  6 ″ ″

97 8.1 623.1  7 ″ ″

95 8.1 588.2  8 ″ ″

19 8.1 535.2  9 ″ ″

99 8.5 622.2  10 ″ ″

80 8.4 611.2  11 ″ ″

99 8.2 569.2  12 ″ ″

93 8.9 656.2  13 ″ ″

85 9.1 697.0  14 ″ ″

95 8.7 611.2  15 ″ ″

87 7.8 573.2  16 ″ ″

100 8.4 653.2  17 ″ ″

97 8.6 611.1  18 ″ ″

99 8.7 636.3  19 ″ ″

83 7.2 621.2  20 ″ ″

98 7.4 595.2  21 ″ ″

84 7.4 536.3  22 ″ ″

99 8.4 614.3  23 ″ ″

63 8.2 570.2  24 ″ ″

92 7.5 572.3  25 ″ ″

93 8.4 606.4  26 ″ ″

96 7.4 582.3  27 ″ ″

93 8.1 624.2  28 ″ ″

93 7.8 602.2  29 ″ ″

95 7.4 585.2  30 ″ ″

87.39 4.0 516.4  31 ″ ″

92 5.5 560.3  32 ″ ″

90 5.7 563.3  33 ″ ″

87.73 5.6 625.4  34 ″ ″

85.41 6.0 565.4  35 ″ ″

98.4 6.4 671.1  36 ″ ″

86 4.9 542.3  37 ″ ″

89 6.1 572.3  38 ″ ″

77.61 6.8 555.4  39 ″ ″

89.16 4.2 545.4  40 ″ ″

92.32 5.3 599.3  41 ″ ″

83 6.0 589.2  42 ″ ″

36.3 5.9 531.2  43 ″ ″

83.27 5.9 555.3  44 ″ ″

82 4.5 564.4  45 ″ ″

86.75 6.0 577.3  46 ″ ″

91.95 4.7 501.4  47 ″ ″

88.94 4.5 475.3  48 ″ ″

73 5.3 542.3  49 ″

90.96 4.4 486.4  50 ″ ″

95.5 5.9 530.4  51 ″ ″

94.51 6.1 533.4  52 ″ ″

93.64 6.0 595.4  53 ″ ″

96.05 6.5 535.4  54 ″ ″

84.68 6.9 641.1  55 ″ ″

86 5.5 512.3  56 ″ ″

92 6.5 542.4  57 ″ ″

91.29 7.2 525.5  58 ″ ″

94.7 4.7 515.4  59 ″ ″

94 5.8 569.3  60 ″ ″

89.43 6.6 559.3  61 ″ ″

32 6.9 501.5  62 ″ ″

93.53 6.4 525.4  63 ″ ″

94.7 4.9 534.4  64 ″ ″

94.32 6.4 547.3  65 ″ ″

91.71 5.2 471.4  66 ″ ″

92.47 5.0 445.4  67 ″ ″

58 59 512.3  68 ″

84.55 3.6 559.4  69 ″ ″

87.7 4.7 603.4  70 ″ ″

90.77 4.8 606.4  71 ″ ″

72.34 4.8 668.4  72 ″ ″

87.18 5.1 608.4  73 ″ ″

69.52 5.4 714.1  74 ″ ″

63.39 4.2 585.3  75 ″ ″

54.46 5.1 615.4  76 ″ ″

87.3 5.7 598.4  77 ″ ″

96.1 3.8 588.4  78 ″ ″

89.9 4.5 642.3  79 ″ ″

61.5 5.1 632.3  80 ″ ″

43.65 5.0 574.3  81 ″ ″

88.18 5.0 598.3  82 ″ ″

88.6 4.0 607.4  83 ″ ″

90.08 5.1 620.3  84 ″ ″

85.57 4.0 544.3  85 ″ ″

48.41 4.5 585.3  86 ″

82.68 6.1 589.3  87 ″ ″

79.99 6.5 611.4  88 ″ ″

86.07 4.8 503.4  89 ″ ″

82 5.1 551.4  90 ″ ″

19.44 4.4 502.4  91 ″ ″

86.48 5.1 550.4  92 ″ ″

80 6.3 567.3  93 ″

94.62 6.6 559.3  94 ″ ″

57.01 6.9 581.4  95 ″ ″

92 5.2 473.4  96 ″ ″

87.4 5.6 521.4  97 ″ ″

20.99 5.0 472.4  98 ″ ″

88.63 5.7 520.4  99 ″ ″

84 6.7 537.3 100 ″

89.71 5.2 632.3 101 ″ ″

90.25 5.5 654.4 102 ″ ″

90.09 4.0 546.4 103 ″ ″

71 4.4 594.3 104 ″ ″

37.19 3.8 545.3 105 ″ ″

76.55 4.5 593.4 106

69.62 5.9 405.2 107

″ 98 7.1 493.2 108

″ 80 6.0 467.3 109

″ 88 6.5 471.2 110

″ 60.04 5.7 427.3 111

″ 78 6.5 515.2 112

″ 97 6.2 455.2 113

″ 70 5.7 489.3 114

″ 90 6.2 493.3 115

62.88 3.6 305.3 116

″ 82.99 4.7 393.2 117

″ 74.42 5.0 393.1 118

″ 10.53 5.4 367.3 119

″ 74.79 4.3 371.2 120

″ 50.14 3.4 327.3 121

″ 70 4.3 415.2 122

″ 84 3.9 355.3 123

″ 66 3.5 389.3 124

″ 94.61 3.9 393.2 125

71 5.5 462.3 126

″ 52 6.6 550.2 127

″ 57 6.8 550.1 128

″ 60 5.6 524.2 129

″ 64 6.1 528.2 130

″ 27 5.4 484.3 131

″ 51 6.2 572.2 132

″ 73 5.7 512.2 133

″ 61 5.4 546.2 134

″ 43 5.8 550.2 135

76 5.3 483.3 136

″ 49 6.4 571.2 137

″ 63 6.6 571.1 138

″ 79 5.4 545.2 139

″ 57 5.9 549.2 140

″ 66.58 5.2 505.3 141

″ 61 6.0 593.2 142

″ 67 5.5 533.2 143

″ 61 5.2 567.3 144

″ 51 5.6 571.2 145

56 7.0 457.3 146

″ 64 8.1 545.2 147

″ 52 8.3 545.2 148

″ 69 7.1 519.3 149

″ 70 7.6 523.3 150

″ 63.77 6.7 479.4 151

″ 50 7.3 567.3 152

″ 46 7.3 507.3 153

″ 78 6.7 541.3 154

″ 66 7.0 545.3 155

68 6.0 457.2 156

″ 65 7.1 545.2 157

″ 67 7.3 545.1 158

″ 66 6.1 519.2 159

″ 77 6.6 523.2 160

″ 60.49 5.8 479.3 161

″ 60 6.6 567.3 162

″ 69 6.2 507.2 163

″ 50 5.8 541.2 164

″ 49 6.2 545.2 165

67 4.4 466.3 166

″ 45 5.5 554.2 167

″ 65.89 5.7 554.1 168

″ 5 5.4 528.2 169

″ 64.08 5.0 532.2 170

″ 62.51 4.3 488.3 171

″ 55 5.2 576.3 172

″ 50.35 4.7 516.3 173

″ 7 5.2 550.3 174

″ 48.63 4.8 554.3 175

53 5.7 459.2 176

″ 49 6.9 547.2 177

″ 61 7.1 547.1 178

″ 57 5.9 521.2 179

″ 65 6.4 525.2 180

″ 88.99 5.6 481.3 181

″ 58 6.4 569.2 182

″ 64 6.0 509.2 183

″ 63 6.0 547.2 184

67.83 10.1 516.3 185

″ 61.66 6.7 525.3 186

″ 40.48 9.9 537.3 187

″ 50 6.4 546.3 188

″ 42.57 7.4 478.4 189

″ 29 4.8 487.3 190

″ 55 10.3 499.3 191

″ 19.39 6.7 508.3 192

″ 67 11.1 567.3 193

″ 64.73 7.9 576.3 194

92 10.6 586.3 195

″ 85 7.3 595.3 196

″ 96 10.5 607.3 197

″ 89.25 7.2 616.3 198

″ 98.24 7.9 548.3 199

″ 94 5.6 557.3 200

″ 98 10.8 569.2 201

″ 93.17 7.3 578.2 202

″ 97.82 11.7 637.3 203

″ 88.11 8.5 646.3 204

73 11.2 690.0 205

″ 60.44 7.9 699.0 206

″ 76 11.1 711.0 207

″ 72.2 7.8 720.0 208

″ 89.42 8.5 652 209

″ 48 6.2 659.0 210

″ 78.2 11.6 673.0 211

″ 66.1 7.9 682.0 212

″ 78 12.6 739.1 213

″ 88.77 9.1 750.0 214

73 10.6 604.3 215

″ 67 7.5 613.2 216

″ 73 10.5 625.3 217

″ 83 7.3 634.2 218

″ 87.32 7.9 566.3 219

″ 79 5.7 575.2 220

″ 89 10.7 587.2 221

″ 78.75 7.4 596.2 222

″ 95 11.6 655.3 223

″ 79 8.6 664.3 224

58 9.4 614.2 225

″ 78 6.4 623.2 226

″ 75 9.2 635.3 227

″ 88 6.1 644.3 228

″ 86 6.7 576.3 229

″ 80 4.6 585.2 230

″ 73 9.5 597.2 231

″ 66 6.2 606.2 232

″ 62 10.5 665.3 233

″ 81 7.5 674.3 234

92 8.9 540.3 235

″ 86 5.6 549.2 236

″ 91 8.7 561.3 237

″ 94.51 5.4 570.2 238

″ 93.36 6.2 502.3 239

″ 97 3.8 511.3 240

″ 98.13 9.0 523.3 241

″ 82 5.4 532.2 242

″ 99 10.1 591.3 243

″ 94.74 6.8 600.3 244

89 9.8 596.3 245

″ 81 6.6 605.3 246

″ 96 9.7 617.3 247

″ 85.68 6.4 626.3 248

″ 98.65 7.1 558.3 249

″ 92 4.8 567.2 250

″ 96 10.0 579.2 251

″ 88.12 6.5 588.2 252

″ 97 10.9 647.3 253

″ 86 7.8 656.3 254

79 10.1 572.2 255

″ 79 7.0 581.2 256

″ 71 10.0 593.3 257

″ 72.74 6.6 602.2 258

″ 79.1 7.4 534.3 259

″ 74 4.9 543.2 260

″ 84.17 10.3 555.2 261

″ 76.16 6.7 564.2 262

″ 95 11.1 623.3 263

″ 78.91 8.0 632.3 264

75.26 5.1 430.2 265 ″

″ 90.43 5.0 430.3 266 ″

″ 74.93 4.3 452.3 267 ″

″ 79.62 4.9 390.3 268 ″

″ 92.82 5.6 490.4 269 ″

″ 68.87 3.6 421.3 270 ″

″ 79.07 4.9 440.2 271 ″

″ 84.22 3.0 392.3 272 ″

″ 67.34 4.9 418.2 273 ″

″ 81.63 4.4 352.3 274 ″

″ 90.11 4.7 342.3 275 ″

″ 54.36 4.3 438.3 276 ″

″ 81.69 4.9 432.2 277 ″

″ 85.62 5.2 382.3 278 ″

″ 86.19 3.2 377.3 279

″ 94.76 4.9 451.2 280 ″

″ 99.42 4.7 451.3 281 ″

″ 90.55 4.0 473.3 282 ″

″ 93.80 4.6 411.3 283 ″

″ 82.71 5.4 511.4 284 ″

″ 90.85 3.4 442.3 285 ″

″ 98.65 4.6 461.2 286 ″

″ 98.80 2.8 404.3 287 ″

″ 86.02 4.6 439.3 288 ″

″ 97.47 4.1 373.3 289 ″

″ 99.31 4.4 363.3 290 ″

″ 45.77 4.1 459.3 291 ″

″ 94.07 4.6 453.3 292 ″

″ 95.65 5.0 403.4 293 ″

″ 94.30 2.9 398.3 294

″ 80.64 5.9 481.2 295 ″

″ 98.05 5.7 481.3 296 ″

″ 94.93 5.0 503.4 297 ″

″ 96.81 5.6 441.3 298 ″

″ 95.00 6.3 541.4 299 ″

″ 95.13 4.2 472.4 300 ″

″ 52.68 3.2 452.4 301 ″

″ 98.03 5.6 491.2 302 ″

″ 96.44 3.7 217.9 303 ″

″ 97.22 5.6 469.3 304 ″

″ 96.97 5.2 403.3 305 ″

″ 99.05 5.4 393.4 306 ″

″ 32.67 5.1 489.3 307 ″

″ 84.51 5.6 483.3 308 ″

″ 98.44 6.0 433.4 309 ″

″ 97.78 4.0 428.3 310

″ 79.54 5.0 460.2 311 ″

″ 78.59 4.9 460.3 312 ″

″ 66.24 4.2 482.3 313 ″

″ 70.15 4.8 420.3 314 ″

″ 57.87 5.5 520.4 315 ″

″ 71.26 3.6 451.3 316 ″

″ 81.16 4.8 470.2 317 ″

″ 74.96 2.9 413.3 318 ″

″ 53.47 4.8 448.3 319 ″

″ 87.88 4.3 382.3 320 ″

″ 91.41 4.6 372.3 321 ″

″ 1.59 5.0 468.3 322 ″

″ 77.81 4.8 462.3 323 ″

″ 76.59 5.1 412.3 324 ″

″ 83.35 3.1 407.3 325

87.42 5.2 444.2 326 ″

″ 98.89 5.1 444.3 327 ″

″ 95.68 4.3 466.3 328 ″

″ 97.27 4.9 404.3 329 ″

″ 95.73 5.7 504.4 330 ″

″ 83.37 3.7 435.3 331 ″

″ 71.88 3.2 413.3 332 ″

″ 98.33 5.0 454.2 333 ″

″ 83.73 3.0 397.3 334 ″

″ 94.77 5.0 432.3 335 ″

″ 95.88 4.5 366.3 336 ″

″ 98.9 4.7 356.3 337 ″

″ 50.74 4.4 452.3 338 ″

″ 95.39 5.0 446.3 339 ″

″ 98.2 5.3 396.3 340 ″

″ 92.35 3.2 391.3 341

90.41 5.1 444.2 342 ″

″ 87.41 5.0 444.3 343 ″

″ 87.37 4.3 466.3 344 ″

″ 83.01 4.9 404.3 345 ″

″ 89.47 5.6 504.4 346 ″

″ 77.55 3.6 435.3 347 ″

″ 49.49 2.4 414.3 348 ″

″ 85.63 4.9 454.2 349 ″

″ 88.12 2.9 397.3 350 ″

″ 87.73 4.9 432.3 351 ″

″ 84.48 4.4 366.3 352 ″

″ 82.03 4.7 356.3 353 ″

″ 82.93 4.9 446.3 354 ″

″ 72.6 5.3 396.3 355 ″

″ 86.75 3.2 391.3 356

″ 93.75 4.7 413.1 357 ″

″ 96.13 4.6 413.2 358 ″

″ 98.3 3.8 435.2 359 ″

″ 96.45 4.5 373.2 360 ″

″ 97.9 5.3 473.4 361 ″

″ 97.57 3.0 404.3 362 ″

″ 78.0 2.5 383.2 363 ″

″ 98.96 4.5 423.1 364 ″

″ 93.98 2.4 366.3 365 ″

″ 97.98 4.5 401.2 366 ″

″ 93.33 4.0 335.2 367 ″

″ 95.73 4.3 325.3 368 ″

″ 1.21 3.9 421.3 369 ″

″ 88.55 4.6 415.2 370 ″

″ 95.93 4.9 365.3 371 ″

″ 99.1 2.6 360.2 372

″ 90.59 3.4 392.1 373 ″

″ 93.57 3.3 392.2 374 ″

″ 97.23 2.6 414.2 375 ″

″ 93.83 3.1 352.3 376 ″

″ 96.81 4.0 452.4 377 ″

″ 97.7 2.2 383.3 378 ″

″ 53.69 3.3 362.2 379 ″

″ 97.1 3.1 402.1 380 ″

″ 70.3 2.5 345.3 381 ″

″ 97.59 3.1 380.2 382 ″

″ 86.74 2.4 314.2 383 ″

″ 87.28 2.6 304.3 384 ″

″ 10.27 3.1 400.2 385 ″

″ 93.38 3.1 394.2 386 ″

″ 88.99 3.4 344.3 387 ″

″ 89.43 2.5 339.3 388

86.18 4.2 458.3 389 ″

″ 37.01 3.9 404.3 390 ″

″ 57.02 2.7 437.4 391 ″

″ 78.70 4.3 441.3 392 ″

″ 67.94 4.6 490.3 393 ″

″ 39.75 4.5 479.3 394 ″

″ 94.48 2.8 435.4 395 ″

″ 83.7 3.4 432.3 396 ″

″ 96.5 4.7 464.4 397 ″

″ 43.75 4.5 547.3 398

″ 86.87 3.3 399.3 399 ″

″ 47.77 2.9 345.3 400 ″

″ 82 3.4 382.3 401 ″

″ 97.10 3.8 431.2 402 ″

″ 76.92 3.8 420.2 403 ″

″ 97.3 2.8 373.3 404 ″

″ 95.9 4.0 405.3 405 ″

″ 69.50 3.7 488.3 406

″ 90.79 4.1 420.3 407 ″

″ 86.38 2.5 399.3 408 ″

″ 67.52 4.6 452.2 409 ″

″ 99.8 2.7 397.3 410 ″

″ 97.7 3.3 394.3 411

″ 87.97 5.0 488.3 412 ″

″ 97.23 3.6 467.4 413 ″

″ 99.29 3.7 465.4 414 ″

″ 96.2 4.2 462.4 415 ″

″ 72.0 5.5 494.3 416

″ 85.09 4.3 467.3 417 ″

″ 68.52 4.1 413.3 418 ″

″ 98.76 2.8 446.4 419 ″

″ 73.21 4.4 450.3 420 ″

″ 76.94 4.7 499.2 421 ″

″ 85.12 4.6 488.2 422 ″

″ 98.15 2.9 444.4 423 ″

″ 58 5.1 477.3 424 ″

″ 25 3.6 410.3 425 ″

″ 69.90 4.6 556.3 426

90.11 8.2 556.3 427 ″

″ 95.30 9.7 552.3 428 ″

″ 89.35 9.6 573.3 429 ″

″ 97.48 11.8 547.4 430 ″

″ 91.35 9.6 591.3 431 ″

″ 66.60 9.7 557.3 432 ″

″ 97.25 10.5 547.3 433 ″

″ 98.20 10.2 549.3 434

″ 88.28 4.7 489.3 435 ″

″ 94.30 5.8 485.3 436 ″

″ 92.92 5.6 506.3 437 ″

″ 95.73 7.1 480.4 438 ″

″ 89.80 5.6 524.3 439 ″

″ 69.38 5.6 490.3 440 ″

″ 95.21 6.2 480.3 441 ″

″ 96.98 6.0 482.3 442

85.00 5.4 456.3 443 ″

″ 94.40 6.5 452.3 444 ″

″ 91.10 6.3 473.3 445 ″

″ 96.60 7.7 447.3 446 ″

″ 92.80 6.3 491.2 447 ″

″ 85.40 6.3 457.2 448 ″

″ 96.70 6.9 447.2 449 ″

″ 98 6.7 449.2 450

″ 38.17 3.6 385.2 451 ″

″ 92.70 3.4 406.2 452 ″

″ 89.50 4.7 380.3 453 ″

″ 86.24 3.4 424.2 454 ″

″ 71.20 3.3 390.2 455 ″

″ 88.60 3.8 380.2 456 ″

″ 89.26 3.5 382.2 457

″ 96.55 4.9 445.3 458 ″

″ 94.46 4.8 455.2 459 ″

″ 95.6 4.7 411.3 460 ″

″ 98.1 5.0 461.3 461 ″

″ 93.31 5.1 419.4 462 ″

″ 97.08 4.2 402.3 463 ″

″ 94.61 4.4 395.3 464 ″

″ 97.05 4.9 503.2 465 ″

″ 95.13 5.1 453.4 466

″ 93.21 4.8 475.3 467 ″

″ 94.08 4.7 485.2 468 ″

″ 93.08 4.6 441.3 469 ″

″ 95.17 4.9 491.3 470 ″

″ 89.99 5.0 449.4 471 ″

″ 92 4.1 432.3 472 ″

″ 94.71 4.3 425.3 473 ″

″ 95.3 4.8 533.2 474 ″

″ 94.13 5.0 483.4 475

″ 95 5.1 459.3 476 ″

″ 94.69 5.0 469.2 477 ″

″ 94.44 4.9 425.3 478 ″

″ 98 5.2 475.3 479 ″

″ 96.2 5.3 433.4 480 ″

″ 93 4.4 416.3 481 ″

″ 94.59 4.6 409.3 482 ″

″ 95.22 5.1 517.2 483 ″

″ 95.7 5.3 467.4 484

″ 94.8 4.6 457.2 485 ″

″ 86.7 4.5 420.3 486 ″

″ 88.5 4.8 447.3 487 ″

″ 96.9 5.1 483.4 488 ″

″ 92.3 4.7 505.2 489

″ 65.4 4.9 471.2 490 ″

″ 62.6 4.7 434.3 491 ″

″ 57.9 5.0 461.3 492 ″

″ 94.2 5.3 497.4 493 ″

″ 54.0 5.0 519.2 494

″ 54.6 4.8 501.3 495 ″

″ 64.9 4.7 464.3 496 ″

″ 70.4 4.9 491.3 497 ″

″ 96.5 5.2 527.4 498 ″

″ 55.7 4.9 549.2 499

″ 57.4 5.1 485.3 500 ″

″ 59.3 4.9 448.4 501 ″

″ 53.6 5.2 475.3 502 ″

″ 97.8 5.4 511.4 503 ″

″ 10 +36.87 5.2 533.2 504

96.33 11.2 646.3 505 ″

″ 92.67 9.4 690.1 506 ″

″ 41.11 9.5 656.2 507 ″

″ 97.65 10.1 646.2 508 ″

″ 96.29 9.9 648.2 509

90.89 8.5 501.3 510 ″ ″

61.04 5.8 401.2 511 ″

99.16 10.5 496.4 512 ″ ″

95.73 7.1 396.3 513 ″

66 9.3 496.3 514 ″ ″

95.00 8.9 396.2 515 ″

96.61 9.5 530.3 516 ″ ″

94.05 6.4 430.3 517 ″

87 8.6 536.3 518 ″ ″

91.59 5.6 436.3 519

86.84 8.4 522.3 520 ″ ″

94.18 5.4 422.3 521 ″

99.75 10.4 517.4 522 ″ ″

96.8 6.8 417.4 523 ″

70.34 9.1 517.3 524 ″ ″

93.49 5.8 417.3 525 ″

93.03 9.3 551.3 526 ″ ″

97.13 6.1 451.3 527 ″

74.37 8.4 557.3 528 ″ ″

92.92 5.3 457.3 529

92.92 8.8 484.3 530 ″ ″

92.68 5.5 384.2 531 ″

98.29 10.8 479.3 532 ″ ″

96.39 7.0 379.3 533 ″

99 9.5 479.2 534 ″ ″

99.76 6.0 379.2 535 ″

99.17 9.7 513.2 536 ″ ″

99.74 6.3 413.2 537 ″

68.71 8.7 519.3 538 ″ ″

90.09 5.4 419.3 539

91.37 9.8 552.3 540 ″ ″

95.39 6.6 452.3 541 ″

98.71 11.7 547.4 542 ″ ″

99.02 7.9 447.4 543 ″

79.38 10.5 547.3 544 ″ ″

95.46 7.1 447.3 545 ″

95.3 10.6 581.3 546 ″ ″

95.45 7.3 481.3 547 ″

80.92 9.8 587.3 548 ″ ″

92.06 6.5 487.3 549

63 7.7 529.4 550 ″ ″

79 7.1 495.4 551 ″

70 6.7 529.3 552 ″ ″

77 6.3 495.3 553 ″

61 6.9 563.3 554 ″ ″

69 6.5 529.3 555 ″

69 6.1 569.3 556 ″ ″

76 5.8 535.3 557

79 5.9 555.3 558 ″ ″

88 5.6 521.3 559 ″

90.81 7.4 550.4 560 ″ ″

95.6 6.9 516.4 561 ″

80.85 6.4 550.3 562 ″ ″

85.8 6.0 516.3 563 ″

92.92 6.6 584.3 564 ″ ″

97.26 6.3 550.3 565 ″

82.91 5.8 590.3 566 ″ ″

87.77 5.5 556.3 567

86 6.0 517.3 568 ″ ″

83.41 5.7 483.3 569 ″

95 7.6 512.3 570 ″ ″

94.08 7.1 478.4 571 ″

87.39 6.5 512.3 572 ″ ″

90.06 6.1 478.3 573 ″

85.61 6.8 546.2 574 ″ ″

83.51 6.4 512.3 575 ″

78.63 5.9 552.3 576 ″ ″

79.58 5.6 518.3 577

84 7.1 585.3 578 ″ ″

91 6.7 551.3 579 ″

89.59 8.6 580.4 580 ″ ″

97.13 7.9 546.4 581 ″

83 7.6 580.3 582 ″ ″

92.05 7.1 546.3 583 ″

86 7.8 614.3 584 ″ ″

95.49 7.3 580.3 585 ″

77 7.0 620.3 586 ″ ″

91.1 6.6 586.4 587

95 4.6 435 588 ″

″ 90 4.4 391.3 589 ″

″ 88 5.1 435.3 590 ″

″ 92 4.9 447.3 591 ″

″ 20.32 5.1 399.4 592

″ 85 5.3 486.3 593 ″

″ 97 5.1 442.3 594 ″

″ 92 5.7 486.4 595 ″

″ 79 5.5 498.3 596

″ 93.4 4.68 451.29 597 ″

″ 94.9 4.86 425.27 598 ″

″ 97.9 5.37 475.22 599 ″

″ 97.1 5.20 457.32 600 ″

″ 95.1 5.10 441.24 601

″ 91.1 4.61 481.29 602 ″

″ 97.5 4.78 455.29 603 ″

″ 98.0 5.28 505.22 604 ″

″ 95.4 5.12 487.33 605 ″

″ 94.0 5.03 471.27 606

″ 89.8 4.86 465.29 607 ″

″ 98.2 5.03 439.29 608 ″

″ 97.6 5.53 489.24 609 ″

″ 93.3 5.36 471.34 610 ″

″ 91.4 5.27 455.26 611

94 4.9 459.3 612 ″

″ 92.95 4.8 469.2 613 ″

″ 91.61 4.7 425.3 614 ″

″ 92 5.0 475.3 615 ″

″ 85.2 5.1 433.4 616 ″

″ 83 4.2 416.3 617 ″

″ 94.11 4.4 409.3 618 ″

″ 93.85 5.0 517.2 619 ″

″ 92.74 5.1 467.4 620

″ 91 4.8 489.3 621 ″

″ 91.9 4.7 499.3 622 ″

″ 89.71 4.6 455.3 623 ″

″ 90 4.9 505.3 624 ″

″ 83.96 5.0 463.4 625 ″

″ 87 4.1 446.3 626 ″

″ 93.1 4.3 439.3 627 ″

″ 93.21 4.8 547.2 628 ″

″ 90.67 5.0 497.4 629

″ 79.6 4.9 485.2 630 ″

″ 72.8 4.8 448.3 631 ″

″ 78.7 5.1 475.3 632 ″

″ 97.3 5.4 511.4 633 ″

″ 51.5 5.1 533.2 634

″ 76.1 4.9 515.3 635 ″

″ 74.2 4.7 478.3 636 ″

″ 76.5 5.0 505.3 637 ″

″ 97.7 5.3 541.4 638 ″

″ 71.4 5.0 563.2 639

″ 82.54 4.4 451.3 640 ″

″ 93.42 4.2 397.3 641 ″

″ 98.93 2.9 430.4 642 ″

″ 81.46 4.5 434.3 643 ″

″ 96.41 4.9 483.3 644 ″

″ 91.55 4.7 472.3 645 ″

″ 97.96 2.9 428.4 646 ″

″ 96.9 5.0 425.3 647 ″

″ 95.8 4.9 457.3 648 ″

″ 91.41 4.6 540.3 649

″ 88.0 4.75 465.3 650 ″

″ 99.0 4.89 439.3 651 ″

″ 98.5 5.42 489.2 652 ″

″ 93.3 5.24 471.3 653 ″

″ 87.6 5.14 455.3 654

″ 88.3 4.66 495.3 655 ″

″ 98.1 4.82 469.3 656 ″

″ 98.4 5.34 519.2 657 ″

″ 95.4 5.16 501.3 658 ″

″ 89.8 5.08 485.3 659

80.76 4.84 410.2 660 ″

″ 61.69 4.97 426.2 661 ″

″ 90.93 4.79 454.1 662 ″

″ 91.55 4.58 394.2 663 ″

″ 91.99 4.88 454.1 664 ″

″ 92.79 5.55 526.2 665 ″

″ 93.78 5.02 502.1 666 ″

″ 96.3 4.75 408.2 667 ″

″ 81.2 5.02 408.2 668

″ 90.79 4.74 440.2 669 ″

″ 78.93 4.88 456.3 670 ″

″ 91.87 4.69 484.2 671 ″

″ 91.19 4.51 424.2 672 ″

″ 95.27 4.79 484.2 673 ″

″ 89.5 5.46 542.2 674 ″

″ 90.77 4.92 532.1 675 ″

″ 95.1 4.66 438.2 676 ″

″ 88.7 4.92 524.2 677

″ 81.65 4.99 424.2 678 ″

″ 70.32 5.11 440.3 679 ″

″ 90.06 4.96 468.2 680 ″

″ 94.11 4.74 408.2 681 ″

″ 93.96 5.02 468.2 682 ″

″ 93.3 5.66 540.2 683 ″

″ 94.79 5.16 516.1 684 ″

″ 96.5 4.9 422.3 685 ″

″ 88.2 5.19 438.2 686

87.93 4.86 424.2 687 ″

″ 84.74 5 440.2 688 ″

″ 95.34 4.82 468.2 689 ″

″ 89.78 4.6 408.2 690 ″

″ 95.16 4.9 468.1633 691 ″

″ 95.6 5.56 540.2 692 ″

″ 95.24 5.05 516.3 693 ″

″ 96.6 4.8 422.2 694 ″

″ 90.4 5.04 438.2 695

″ 93.12 4.78 454.2 696 ″

″ 86.11 4.92 470.3 697 ″

″ 94.89 4.73 498.2 698 ″

″ 94.1 4.54 438.3 699 ″

″ 95.66 4.81 498.2 700 ″

″ 94.8 5.48 570.2 701 ″

″ 93.63 4.96 546.1 702 ″

″ 96.7 4.7 452.3 703 ″

″ 85.6 4.96 468.2 704

78.36 3.14 359.1 705

″ 47.4 3.9 367.1 706

″ 69.72 4.28 385.2 707

″ 34.86 4.96 393.2 708

″ 37.54 4.91 449.2 709

″ 81.57 4.46 483.1 710

″ 55.98 5.12 491.1 711

″ 73.74 3.09 441.2 712

″ 40.19 2.85 449.2 713

″ 90.07 3.18 426.2 714

″ 74.98 3.84 434.2 715

″ 78.14 4.24 397.2 716

″ 39.87 4.92 405.2 717

″ 57.34 4.45 477.2 718

″ 37.75 5.01 485.1 719

70.3 5.2 412.1 720 ″ ″

70.7 5.0 386.1 721 ″ ″

61.9 6.3 600.3 722 ″

″ 49.3 6.1 538.4 723

65.0 5.1 412.2 724 ″ ″

44.3 4.9 386.2 725 ″ ″

49.2 6.2 600.3 726 ″

″ 37.5 6.0 538.4 727

87.1 5.1 468.1 728 ″ ″

84.4 4.9 442.1 729 ″ ″

82.3 6.2 656.3 730 ″

93.8 4.7 406.3 731 ″ ″

80.7 4.6 380.3 732 ″ ″

84.1 5.9 594.3 733

67.9 4.7 462.1 734 ″ ″

66.9 4.6 436.1 735 ″ ″

56.8 5.9 650.2 736 ″

88.1 4.3 400.3 737 ″ ″

82.8 4.1 374.3 738 ″ ″

51.4 5.6 588.3 739

77.7 5.1 446.2 740 ″ ″

76.1 4.9 420.2 741 ″ ″

67.1 6.2 634.3 742 ″

88.9 4.7 384.3 743 ″ ″

79.3 4.5 358.3 744 ″ ″

65.1 5.9 572.4 745

80.0 4.0 398.3 746 ″ ″

76.9 3.8 372.3 747 ″ ″

42.7 5.8 586.4 748 ″ ″

64.6 4.4 483.3 749 ″

87.4 5.3 409.3 750 ″ ″

71.0 5.1 383.3 751 ″ ″

59.8 6.7 597.4 752 ″ ″

84.4 5.6 494.3 753

80.1 3.9 398.3 754 ″ ″

63.1 3.7 372.3 755 ″ ″

64.4 4.3 483.3 756 ″

84.6 5.3 409.3 757 ″ ″

59.6 5.0 383.3 758 ″ ″

52.9 6.6 597.4 759 ″ ″

81.6 5.5 494.3 760

″

75.3 5.3 465.3 761 ″ ″

60.3 5.1 439.3 762 ″ ″

61.8 6.6 653.4 763 ″ ″

74.4 5.6 550.3 764

74.5 3.6 448.2 765 ″ ″

51.3 3.4 422.2 766 ″ ″

58.8 3.9 533.2 767 ″

86.2 4.8 459.3 768 ″ ″

63.2 4.6 433.3 769 ″ ″

60.1 6.2 647.4 770 ″ ″

83.5 5.1 544.2 771

68.1 4.1 432.3 772 ″ ″

63.8 3.9 406.2 773 ″ ″

41.1 5.8 620.4 774 ″ ″

62.8 4.4 517.2 775 ″

85.5 5.4 443.3 776 ″ ″

62.5 5.2 417.3 777 ″ ″

66.0 6.7 631.4 778 ″ ″

87.7 5.6 528.3Pharmacological Study

The compounds of the present invention can and have been tested asregards their affinity for different sub-types of somatostatin receptorsaccording to the procedures described below.

Study of the Affinity for the Sub-types of Human Somatostatin Receptors:

The affinity of a compound of the invention for sub-types of humansomatostatin receptors 1 to 5 (sst₁, sst₂, sst₃, sst₄ and sst₅,respectively) is determined by measurement of the inhibition of the bondof [¹²⁵I-Tyr¹¹]SRIF-14 to transfected CHO-K1 cells.

The gene of the sst₁ receptor of human somatostatin has been cloned inthe form of a genomic fragment. A segment PstI-XmnI of 1.5 Kb containing100 bp of the non transcribed 5′ region, 1.17 Kb of the coding region intotality, and 230 bp of the non transcribed 3′ region is modified by theaddition of the linker BglII. The resulting DNA fragment is subcloned inthe BamHI site of a pCMV-81 in order to produce the expression plasmidin mammals (provided by Dr. Graeme Bell, Univ. Chicago). A cloned cellline expressing in a stable fashion the sst₁ receptor is obtained bytransfection in CHO-K1 cells (ATCC) using the calcium phosphateco-precipitation method. The plasmid pRSV-neo (ATCC) is included asselection marker. Cloned cell lines were selected in an RPMI 1640 mediumcontaining 0.5 mg/ml of G418 (Gibco), followed by circular cloning andmultiplication in culture.

The gene of the sst₂ receptor of human somatostatin, isolated in theform of a genomic fragment of DNA of 1.7 Kb BamHI-HindIII and subclonedin a plasmid vector pGEM3Z (Promega), was provided by Dr. G. Bell (Univ.of Chicago). The expression vector of the mammalian cells is constructedby inserting the BamHI-HindII fragment of 1.7 Kb in endonucleaserestriction sites compatible with the plasmid pCMV5. A cloned cell lineis obtained by transfection in CHO-K1 cells using the calcium phosphateco-precipitation method. The plasmid pRSV-neo is included as selectionmarker.

The sst₃ receptor is isolated as a genomic fragment, and the completecoding sequence is contained in a BamHI/HindIII fragment of 2.4 Kb. Theexpression plasmid in mammals, pCMV-h3, is constructed by insertion ofthe NcoI-HindIII fragment of 2.0 Kb in the EcoR1 site of the vector pCMVafter modification of the terminations and addition of EcoR1 linkers. Acloned cell line expressing in a stable fashion the sst₃ receptor isobtained by transfection in CHO-K1 cells (ATCC) by the calcium phosphateco-precipitation method. The plasmid pRSV-neo (ATCC) is included asselection marker. Cloned cell lines were selected in an RPMI 1640 mediumcontaining 0.5 mg/ml of G418 (Gibco), followed by circular cloning andmultiplication in culture.

The expression plasmid of the human sst₄ receptor, pCMV-HX, was Providedby Dr. Graeme Bell (Univ. Chicago). This vector contains the genomicfragment coding for the human sst₄ receptor of 1.4 Kb NheI-NheI, 456 pbof the non transcribed 5′ region, and 200 pb of the non transcribed 3′region, cloned in the XbaI/EcoR1 sites of PCMV-HX. A cloned cell lineexpressing in a stable fashion the sst₄ receptor is obtained bytransfection in CHO-K1 (ATCC) cells by the calcium phosphateco-precipitation method. The plasmid pRSV-neo (ATCC) is included asselection marker. The cloned cell lines were selected in an RPMI 1640medium containing 0.5 mg/ml of G418 (Gibco), followed by circularcloning and multiplication in culture.

The gene corresponding to the human sst₅ receptor, obtained by the PCRmethod using a genomic λ clone as probe, was provided by Dr. Graeme Bell(Univ. Chicago). The resulting PCR fragment of 1.2 Kb contains 21 basepairs of the non transcribed 5′ region, the coding region in totality,and 55 pb of the non transcribed 3′ region. The clone is inserted in anEcoRI site of the plasmid pBSSK(+). The insert is recovered in the formof a HindIII-XbaI fragment of 1.2 Kb for subcloning in an expressionvector in mammals, pCVM5. A cloned cell lines expressing in a stablefashion the sst₅ receptor is obtained by transfection in CHO-K1 cells(ATCC) by the calcium phosphate co-precipitation method. The plasmidpRSV-neo (ATCC) is included as selection marker. The cloned cell lineswere selected in an RPMI 1640 medium containing 0.5 mg/ml of G418(Gibco), followed by circular cloning and multiplication in culture.

The CHO-K1 cells which express in a stable fashion one of the human sstreceptors are cultured in an RPMI 1640 medium containing 10% of foetalcalf serum and 0.4 mg/ml of geneticin. The cells are collected with EDTAat 0.5 mM and centrifuged at 500 g for approximately 5 minutes atapproximately 4° C. The pellet is resuspended in Tris 50 mM buffermedium at pH 7.4 and centrifuged twice at 500 g for approximately 5minutes at approximately 4° C. The cells are lysed by sonication thencentrifuged at 39000 g for approximately 10 minutes at 4° C. The pelletis resuspended in the same buffer and centrifuged at 50000 g forapproximately 10 minutes at approximately 4° C. and the cell membranesin the pellet obtained are stored at −80° C.

The competitive inhibition tests of the bond with [¹²⁵I-Tyr¹¹]SRIF-14are carried out in duplicate in 96-well polypropylene plates. The cellmembranes (10 μg protein/well) are incubated with [¹²⁵1-Tyr¹¹]SRIF-14(0.05 nM) for approximately 60 min. at approximately 37° C. in a HEPES50 mM buffer (pH 7.4) containing BSA 0.2%, MgCl₂ 5 mM, Trasylol 200KIU/ml, bacitricin 0.02 mg/ml and phenylmethylsulphonyl fluoride 0.02mg/ml.

The bound [¹²⁵I-Tyr¹¹]SRIF-14 is separated from the free[¹²⁵I-Tyr¹¹]SRIF-14 by immediate filtration through GF/C glass fibrefilter plates (Unifilter, Packard) pre-impregnated with 0.1% ofpolyethylenimine (P.E.I.), using a Filtermate 196 (Packard). The filtersare washed with 50 mM HEPES buffer at approximately 0-4° C. forapproximately 4 seconds and their radioactivity is determined using acounter (Packard Top Count).

The specific bond is obtained by subtracting the non-specific bond(determined in the presence of 0.1 μM of SRIF-14) from the total bond.The data relative to the bond are analyzed by computer-aided non-linearregression analysis (MDL) and the values of the inhibition constants(Ki) are determined.

Determination of the agonist or antagonist character of a compound ofthe present invention is earned out using the test described below.

Functional Test Inhibition of Production of Intracellular cAMP:

CHO-K1 cells expressing the sub-types of human somatostatin receptors(SRIF-14) are cultured in 24-well plates in an RPMI 1640 medium with 10%of foetal calf serum and 0.4 mg/ml of geneticin. The medium is changedthe day preceding the experiment.

The cells at a rate of 10⁵ cells/well are washed twice with 0.5 ml ofnew RPMI medium comprising 0.2% BSA completed by 0.5 mM of3-isobutyl-1-methylxanthine (IBMX) and incubated for approximately 5 minat approximately 37° C.

-   -   the production of cyclic AMP is stimulated by the addition of 1        mM of forskolin (FSK) for 15-30 minutes at approximately 37° C.    -   the inhibitory effect of the somatostatin of an agonist compound        is measured by the simultaneous addition of FSK (1 μM), SRIF-14        (10⁻¹² M to 10⁻⁶ M) and of the compound to be tested (10⁻¹⁰ M to        10⁻⁵ M).    -   the antagonist effect of a compound is measured by the        simultaneous addition of FSK (1 μM), SRIF-14 (1 to 10 nM) and of        the compound to be tested (10⁻¹⁰ M to 10⁻⁵ M).

The reaction medium is eliminated and 200 ml of 0.1 N HCl are added. Thequantity of cAMP is measured by a radioimmunological test (FlashPlateSMP001A kit, New England Nuclear).

Results:

The tests carried out according to the protocols described above havedemonstrated that the products of general formula (I) defined in thepresent Application have a to good affinity for at least one of thesub-types of somatostatin receptors, the inhibition constant K beinglower than micromolar for certain exemplified compounds.

1. Compounds of the general formula:

in racemic, enantiomeric form or all combinations of these forms, inwhich: R₁ represents a —(CH₂)_(m)—Z₁₂ radical in which Z₁₂ representsoptionally substituted aryl; R₂ represents a radical of formula—C(Y)NHX₁, wherein X₁ represents a (CH₂)_(p)Z₂₂ radical in which Z₂₂represents aryl optionally substituted; R₃ represents an optionallysubstituted alkyl; Y represents an oxygen atom; m is an integer from 1to 6; and p is an integer from 0 to 6; or their addition salts withpharmaceutically acceptable mineral or organic acids.
 2. The compound ofclaim 1, wherein the aryl represented by Z₁₂ is substituted with one ormore fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, —CF₃, —OCF₃,phenyl, phenoxy or aminosulphonyl.
 3. The compound of claim 1, whereinthe aryl represented by Z₂₂ is substituted with one or more fluoro,chloro, bromo, iodo, alkyl, alkenyl, alkoxy, alkylthio, CF₃, OCF₃,nitro, cyano, azido, aminosulphonyl, piperidinosulphonyl, mono- ordi-alkylamino, —C(O)—O-alkyl, —C(O)-alkyl, optionally substitutedphenyl, phenoxy, phenylthio or benzyloxy.
 4. The compound of claim 1,wherein the aryl represented by Z₁₂ is substituted with one or morefluoro, chloro, bromo, iodo, alkyl or alkoxy.
 5. The compound of claim1, wherein the aryl represented by Z₂₂ is substituted with one or morefluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF₃, OCF₃, nitro,cyano, azido, piperidinosulphonyl, —C(O)—O-alkyl, —C(O)-alkyl or phenyl.6. The compound of claim 1, wherein R₃ is unsubstituted alkyl.
 7. Thecompound of claim 1, wherein R₃ is methyl.
 8. The compound of claim 1,wherein Z₁₂ and Z₂₂ are optionally substituted phenyl or naphthyl. 9.The compound of claim 1, wherein m and p are simultaneously
 1. 10. Apharmaceutical composition comprising a compound of claim 1 or anaddition salt thereof with a pharmaceutically acceptable mineral ororganic acid.